Accepted Manuscript Design,synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-Nacetic acid derivatives P. Lakshmi Reddy, M. Lakshmi Devi, S. Satyanarayana, Ashita Singh, T. Veera Reddy, J. Padma Sridevi, G. Raja Sekhar, P. Yogeeswari, D. Sriram, U.S.N. Murty, Ramesh Ummanni, B.V. Subba Reddy, R. Narender PII:

S0223-5234(14)00604-7

DOI:

10.1016/j.ejmech.2014.06.075

Reference:

EJMECH 7118

To appear in:

European Journal of Medicinal Chemistry

Received Date: 27 March 2014 Revised Date:

27 June 2014

Accepted Date: 30 June 2014

Please cite this article as: P. Lakshmi Reddy, M. Lakshmi Devi, S. Satyanarayana, A. Singh, T. Veera Reddy, J. Padma Sridevi, G. Raja Sekhar, P. Yogeeswari, D. Sriram, U.S.N. Murty, R. Ummanni, B.V. Subba Reddy, R. Narender, Design,synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives, European Journal of Medicinal Chemistry (2014), doi: 10.1016/ j.ejmech.2014.06.075. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Research Highlights • A novel tetrasubstituted-1H-pyrrol-1-yl-N-acetic acid derivatives were prepared.

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• Products were screened against M. tuberculosis H37Rv and Mycobacterium smegmatis.

• The cyctotoxicity of TB active compounds were evaluated against HEK-

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293Tcell line.

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• 5n, 5q & 5r showed significant anti-TB activity against M. tuberculosis H37Rv.

• 5d, 5g, 5i & 5j exhibited moderate activity against Mycobacterium

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smegmatis.

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Graphical abstract Design, synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted

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pyrrolyl-N-acetic acid derivatives.

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Design,synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives.

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P. Lakshmi Reddy,a M. Lakshmi Devi,c S. Satyanarayana,a Ashita Singh,b T. Veera Reddy,c J. Padma Sridevi,d G. Raja Sekhar,f P. Yogeeswari,d D. Sriram,d U.S.N.Murty,f Ramesh Ummanni, *b B. V. Subba Reddy,*e R. Narender,*a

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a

Crop Protection Chemicals, Indian Institute of Chemical Technology, Tarnaka,

b

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Hyderabad -500 007, India.

Chemical Biology, Indian Institute of Chemical Technology, Tarnaka,

Hyderabad -500 007, India. c

d

Department of Pharmacy, Birla Institute of Technology & Science-Pilani,

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Hyderabad Campus. e

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Department of Chemistry, Vikrama Simhapuri University, Nellore- 524001.

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Natural Product Chemistry, Indian Institute of Chemical Technology, Tarnaka,

Hyderabad -500 007, India. f

Biology Division Indian Institute of Chemical Technology, Tarnaka,

Hyderabad -500 007, India. CORRESPONDING AUTHOR FOOTNOTE

Email: [email protected] Fax: (+91) 40-27193382 2

ACCEPTED MANUSCRIPT ABSTRACT

A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following

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Paal-Knorr’s approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q & 5r are

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found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 µM. Conversely, these

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compounds showed low cytotoxicity (selectivity index: >16.83) against HEK293T cell line.

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Keywords: Stetter reaction; Paal-Knorr pyrrole synthesis; Anti-mycobacterial activity

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1. Introduction Tuberculosis (TB) is a dreadful disease with high morbidity caused by infection with Mycobacterium tuberculosis. The World Health Organization

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(WHO) estimates 11.4 million people worldwide are infected with both Mycobacterium tuberculosis (Mtb) and HIV. Currently, there are approximately 8 million new infections and 3 million deaths attributed to M. tuberculosis

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annually [1-3]. To date, several anti-tubercular agents in different combinations

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are in clinical application for the treatment. However, patients often develop resistance to commonly used regimen. The expansion of multidrug-resistant TB (MDR-TB) and the emergence of drug-resistant TB (XDR-TB) cause new tackle for the prevention, cure and manage of this lethal disease [4-5].

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Therefore, the development of new drugs with enhanced activity against MDRTB and XDR-TB is highly appreciated for the prevention of disease. Pyrrole has a long history since from its discovery as it presents in many

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naturally occurring chlorophyll, vitamine-B12, and bilirubine. Many of the

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pyrrole derivatives possess a wide range of biological activities such as antimycobacterial [6]. anti-bacterial, anti-inflammatory, anti-oxidant, anti-tumor, CNS depressive, HIV inhibiting and anti-fungal behavior [7]. The Mycobacterial

tuberculosis activity of pyrrole derivative BM212 was first

reported by Deidda et al in 1998 [8]. Later on, several analogues of BM212 have been prepared by Biava and co-workers [9]. In particular, substituted 4

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pyrrole derivatives (LL-3858) are known to exhibit promising MTB activity (Fig. 1). Currently LL-3858 is in phase-II clinical trials in India for the treatment of TB. Thus, 1,2,3,5-tetrasubstituted pyrrole derivatives are very

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important for drug discovery. In addition to pyrrole pharmacopore, benzothiazole and thiadiazole derivatives (Fig. 1) are also an important class of heterocyclic compounds, which display a

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broad spectrum of biological activities such as anti-mycobacterial, antibacterial,

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antifungal, analgesic, anti-inflammatory, antioxidant and antitumor activity [1011]. Based on the pharmcological importance of pyrrole, benzothiazole and thiadiazole derivatives in medicinal chemistry, we report the design, synthesis and anti-mycobacterial activity of novel tetrasubstituted pyrrolyl-N-acetic acid

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and acetamide derivatives (Fig. 2). Preliminary analysis of the structure-activity relationship indicates that the presence of benzothiazole, thiadiazole, pyridine,

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benzyl nucleus and the position of the substituent on pyrrole ring plays a key

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role in biological activity.

Fig. 1 Fig. 2

2. Results and Discussion

2.1 Synthesis

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As a part of our research program on biologically active heterocycles [12]. we herein report an efficient method for the synthesis of tetrasubstituted pyrrolyl-N-acetic acid and acetamide scaffolds. The starting 1,4-diketones were

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prepared through the hydroacylation of α,β-unsaturated ketones (1 mmol) with aromatic or heterocyclic aldehydes (1.2 mmol) in ethanol using 20 mol % of bis-thiazolium salt (0.2 mmol) in the presence of triethyl amine (1 mmol). The

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reaction proceeded smoothly under reflux conditions to afford the

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corresponding 1,4-diketones (Scheme 1) [13]. These 1,4-diketones were then successfully condensed with amino acids to produce the pyrrole derivatives under Paal-Knorr conditions [14-17]. Accordingly, treatment of 1,4-diketone (1) with amino acid (2) in acetic acid under reflux conditions gave the 1,2,3,5-

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tetrasubstituted-1H-pyrrol-1-yl acetic acid derivatives 4a-4k in good yields. This method works well not only with glycine but also with other amino acids

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such as valine and leucine and the results are presented in Table 1. Inspired by their anti-mycobacterial activity, we next attempted the coupling of pyrrolyl-N-

such

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acetic acids with heteroaryl amines. Accordingly, a variety of heteroaryl amines as

benzothiazole,

5-ethyl-1,3,4-thiadiazole,

tryptamine,

and

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aminopyridine were successfully coupled with pyrrolyl-N-acetic acids under amide coupling conditions [18] to produce the corresponding 1,2,3,5tetrasubstituted-1H-pyrrol-1-yl-N-acetamide derivatives 5a, 5b, 5d-o, 5q-t in good yields. Similarly, benzyl amine also coupled with pyrrolyl-N-acetic acid to 6

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produce the corresponding benzamide derivatives 5c and 5p and the results are presented in Table 2 Scheme 1

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Table 1 Table 2

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2.2 Biology

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The anti-mycobacterial activity of the 1,2,3,5-tetrasubstituted pyrrolyl-Nacetamide derivatives 5a-5r was evaluated against Mycobacterium smegmatis, which is a fast growing non-pathogenic strain to assess the activity of the

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compounds in primary screening. It is known in literature that M. smegmatis based screens shows 100% specificity and 78% sensitivity in comparison to MDR Mycobacterium tuberculosis [19-22] The screening results of compounds

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5a-5r (Table 3) reveal that all the tested compounds showed moderate to good

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activity against M.smegmatis. For test compounds, the GI50 is varying largely against M.smegmatis, which is a surrogate model system for identifying new anti-tubercular agents. To determine their exact anti-tubercular potential, all the compounds were further screened against M.tuberculosis (H37Rv). All newly synthesized tetrasubstituted pyrrole derivatives (4a-4k & 5a-5r) were screened in vitro anti-mycobacterial activity against M.tuberculosis H37Rv 7

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(ATCC27294) by agar dilution method [23]. The MIC is defined as the minimum concentration of the compound, which is required to completely inhibit the bacterial growth. The MIC values (µg/mL) of all the compounds (4a-

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4k & 5a-5r) were measured with respect to five standard anti-tubercular drugs at pH 7.4 and the screening results are presented in Table 3 & 4. All new compounds 4a-4k & 5a-5r were screened for in vitro activity against MTB with

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MIC values ranging from 2.97 to 129.87 µM. Among them, sixteen

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tetrasubstituted pyrrole derivatives 4a, 4c, 4g and 5a, 5c, 5e, 5f, 5g, 5h, 5j, 5k, 5m, 5n, 5o, 5q, 5r displayed the MIC values below 24.80 µm. Remarkably, three of them 5n, 5q and 5r inhibited the MTB with MIC value of 3.10 µM, another seven compounds 4c, 4g, 5c, 5e, 5f, 5h, and 5m inhibited the MTB with

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MIC value of 7.95 µM. When compared to first-line TB drug ethambutol (MIC 27.50 µM), ten of these compounds 4c, 4g, 5c, 5e, 5f, 5h, 5m, 5n, 5q and 5r

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were found to be more potent, albeit, they were less effective than other TB drugs including isoniazid (5.25 µM) and rifampicin (0.29 µM).

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The structure reactivity relationship of tested compounds with respect to their anti-tubercular activity reveals that tetrasubstituted pyrrole derivatives 5n, 5q and 5r are highly active due to the presence of naphthalene and two heteroaryl moieties like furan and benzothiazole or thiadiazole. However, the molecules bearing furan and benzothiazole or thiadiazole are not effective (5a, 5b, 5i and 5j) without the naphthalene ring. Similarly, the molecules with 8

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benzothiazole alone are not effective (5f, 5g, 5k and 5l) without furan and naphthalene rings. Furthermore, the molecule with furanyl and 2-naphthyl moieties without heteroaryl ring is also not effective (5p). Conversely, the

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molecule with all three core groups like furan, naphthalene and thiadiazole is also not active. The above study indicates that the position of the substituent on pyrrole ring also plays a crucial role in the observed activity. Next we tested the

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in vitro cytotoxicity of all newly synthesized compounds by 3-(4,5-

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dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) against HEK-293Tcell line at 50 µg/mL concentration [24]. The percentage of cytotoxicity at 50 µM of test compound is provided in Table 5. The compounds which exhibits selectivity index (SI) [25] values greater than 25 in HEK-

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293Tcells are considered as nontoxic. Compounds 5n, 5q and 5r showed 38.32%, 68.83% and 59.68% inhibition at 50 µM/mL with selectivity index of

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>16. Compounds 5b, 5g and 5k were less cytotoxic at 50 µM/mL with favorable selectivity index. These results indicate that compounds 5n, 5q, and

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5r display high activity against M. tuberculosis (2.97, 3.10 µM) and low cytotoxicity against HEK-293Tcell line. Table 3 Table 4 Table 5 9

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3. Conclusion In summary, we have developed a simple method for the synthesis of 2,3,4tetraubstituted-1H-pyrrol-1-ylacetic acid derivatives by means of Paal-Knorr

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approach. The condensation of 1,4-diketone with an excess of amino acid in acetic acid under reflux conditions provides a novel class of 1,2,3,5tetrasubstituted-1H-pyrrol-1-yl-N-acetic acid derivatives. This method also

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describes the synthesis of 1,2,3,5-tetrasubstituted-1H-pyrrol-1-yl acetamide

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derivatives. Among the tested compounds, 5n, 5q & 5r displayed an excellent anti-mycobacterial activity against M. tuberculosis H37Rv using MABA assay, whereas compounds 4c, 4g, 5c, 5e, 5f, 5h, and 5m showed moderate antimycobacterial activity. These pyrrole derivatives showed an interesting anti-

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mycobacterial activity laying the foundation for developing new lead molecules, which may be useful for the drug discovery.

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4.1 Synthesis

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4. Experimental protocols

All chemicals used possess a purity of >95%. Yield refers to pure products after purification and are unoptimized. Melting points were determined in open capillaries on Gallenkamp apparatus and are uncorrected. IR spectra were recorded on a Buck Scientific IR M-500 spectrophotometer in KBr pellets, 1H and 13C NMR spectra for analytical purpose were recorded in CDCl3, DMSO-d6 10

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on a Bruker instrument at 300 MHz and 75 MHz, respectively; chemical shifts are expressed in δ-scale downfield from TMS as an internal standard. Silica gel 60 (230–400 mesh) was used for the column chromatography. TLC plates

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(Silica Gel 60 F254) were used for thin-layer chromatography (TLC). 4.1. General procedure for the preparation of 1,2,3,5-tetrasubstituted

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pyrrolyl-N-acetic acid derivatives.

Following the Paal-Knorr conditions, to a solution of diketone (1 g) in acetic

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acid (10 mL) was added amino acid (2 eq). The resulting mixture was heated in an oil bath at 120 oC. After completion, the mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in equal

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amount of ethyl acetate and water. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography.

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(4a).

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4.1.1 (Table 1): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic acid

White solid, mp: 143-145 °C; Yield: 95%; 1H NMR (300 MHz, CDCl3): δ 7.487.33 (m, 5H, Ar-H), 7.28 (t, J = 6.7 Hz, 3H, Ar-H), 7.22 (d, J = 8.8 Hz, 2H, ArH ), 7.15 (t, J = 6.7 Hz, 1H, Furan-H), 6.40 (s, 1H, Pyrrole- H), 6.38 (d, J = 3.2 Hz, 1H, Furan-H), 6.25 (d, J = 3.2 Hz, 1H, Furan-H) 4.63 (s, 2H, CH2);

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NMR (75 MHz, CDCl3): δ 47.2, 109.8, 111.1, 111.4, 121.3, 126.1, 126.4, 127.8, 11

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127.9, 128.1, 128.7, 129.0, 132.2, 135.4, 136.8, 142.6, 145.6, 175.4; IR (KBr): υ 760, 1069, 1239, 1483, 1728, 2939, 3069 cm-1; ESI-MS: m/z: 366 [M+Na]+; HRMS (ESI) calcd for C22H17NO3Na, 366.1106 [M+Na]+, found: 366.1103. (Table

1):

2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1yl)-3-

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4.1.2

methylbutan oic acid (4b).

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White solid, mp: 121-123 °C; Yield: 69%; 1H NMR (300 MHz, CDCl3): δ 7.56 (t, J=6.7 Hz, 1H, Ar-H) 7.49-7.37(m, 4H, Ar-H), 7.30-7.19 (m, 5H, Ar-H), 7.17

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(d, J = 3.0 Hz, 1H, Furan-H), 6.46 (s, 1H Pyrrole-H), 6.42 (t, J = 3.1 Hz, 1H, Furan-H), 6.38 (d, J = 3.1 Hz, 1H, Furan-H), 4.45 (d, J = 10.5 Hz, 1H, CH), 2.05-1.92 (m, 1H, CH), 0.88 (d, J = 6.2 Hz, 3H, CH3 ), 0.50 (d, J = 6.6 Hz, 3H, 13

C NMR (75MHz, CDCl3): δ 18.6, 21.8, 64.5, 109.0, 111.3, 113.2,

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CH3);

119.4, 125.9, 127.3, 127.6, 127.9, 128.1, 128.5, 129.8, 132.9, 135.4, 138.3, 142.6, 145.1, 176.4; IR (KBr): υ 761, 852, 1232, 1510, 1708, 2843, 3026 cm-1;

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ESI-MS: m/z: 386 [M+H]+.

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4.1.3 (Table 1): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1yl)-3-methyl pent anoic acid (4c).

Brown solid, m.p: 112-114 °C; Yield: 61%; 1H NMR (300 MHz, CDCl3): δ 7.50 (t, J = 7.5 Hz, 3H, Ar-H), 7.42 -7.34 (m, 2H, Ar-H), 7.29 -7.17 (m, 5H, Ar-H), 7.13 (d, J=6.7 Hz, 1H, Furan-H), 6.42 (t, J = 3.0 Hz, 1H, Furan-H), 6.39 (s, 1H, Pyrrole- H), 6.29 (d, J = 3.0 Hz, 1H, Furan-H), 4.91 (dd, J = 4.5, 11.3 Hz, 1H, 12

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CH), 1.61-1.45 (m, 2H, CH2), 0.92-0.81 (m, 1H, CH), 0.61 (d, J = 6.7 Hz, 3H), 0.48 (d, J = 6.0 Hz, 3H); 13C NMR (75MHz, CDCl3): δ 20.9, 22.8, 24.0, 38.9, 57.2, 109.4, 111.5, 112.1, 125.9, 127.5, 127.9, 128.1, 128.6, 128.6, 129.4,

3420 cm-1; ESI-MS: m/z: 400 [M+H]+, 422 [M+Na]+.

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132.9, 137.8, 142.2, 174.7; IR (KBr): υ 759, 1033, 1248, 1511, 1710, 2955,

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4.1.4 (Table 1): 2-(2-3di(furan-2-yl)-5-phenyl-1H-pyrrol-1-yl)acetic acid (4d).

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Brown solid, m.p: 125-127 °C; Yield: 79%; 1H NMR (300 MHz, CDCl3): δ 7.49 (d, J = 1.5 Hz, 1H, Furan-H), 7.42-7.32 (m, 5H, Ar-H), 7.31 (d, J = 1.5 Hz, 1H, Furan-H), 6.55 (d, J = 3.7 Hz, 1H, Furan-H), 6.52 (s, 1H, Pyrrole-H), 6.48 (t, J

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= 5.2 Hz, 1H, Furan-H), 6.29 (t, J = 5.2 Hz, 1H, Furan-H), 6.08 (d, J = 3.7 Hz, 1H, Furan-H), 4.56 (s, 2H, CH2);

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C NMR (75 MHz, CDCl3): δ 47.0, 104.5,

107.8, 109.0, 109.1, 110.9, 111.1, 111.9, 123.2, 127.3, 127.9, 128.4, 128.6,

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128.8, 128.9, 129.0, 136.8, 140.4, 142.8, 174.2; IR (KBr): υ 670, 836, 1017,

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1238, 1486, 1724, 2972, 3059 cm-1; ESI-MS: m/z: 334 [M+H]+; HRMS (ESI) calcd for C20H16O4N 334.1079 [M+H]+, found: 334.1086. 4.1.5

(Table

1):

2-(2-3-di(furan-2-yl)5-phenyl-1H-pyrrol-1yl)-3-

methylbutano ic acid (4e). Brown solid, m.p: 110-112 °C; Yield: 75%; 1H NMR (300 MHz, CDCl3): δ 7.54 (d, J = 6.3 Hz, 2H, Furon-H) 6.49-6.33 (m, 5H, Ar-H), 6.58 (d, J = 4.7 Hz, 13

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1H, Furan-H), 6.57 (s, 1H, Pyrrole-H), 6.49 (t, J = 3.1 Hz, 1H, Furan-H), 6.31 (t, J = 3.1 Hz, 1H, Furan-H), 5.88 (d, J = 3.1 Hz, 1H, Furan-H), 4.41 (s, 1H, CH), 1.98-1.87 (m, 1H, CH), 0.85 (d, J = 6.2 Hz, 3H, CH3), 0.50 (d, J = 6.6 Hz, 13

C NMR (75MHz, CDCl3): δ 18.7, 21.7, 64.5, 104.0, 107.0, 111.0,

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3H,CH3);

111.2, 113.4, 118.4, 118.6, 128.1, 128.6, 129.9, 132.6, 138.4, 140.3, 142.9,

ESI-MS: m/z: 376 [M+H]+, 398 [M+Na]+.

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144.4, 149.9, 176.2; IR (KBr): υ 753, 865, 1246, 1615, 1721, 2867, 3015 cm-1;

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4.1.6 (Table 1): 2-(2-(furan-2-yl)-5-(naphthalene-1-yl)-3-phenyl-1H-pyrrol1-yl)acetic acid (4f).

White solid, m.p: 138-140 °C; Yield: 85%; 1H NMR (300 MHz, CDCl3): δ 7.97

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(d, J = 8.3 Hz, 1H, Ar-H ), 7.81 (d, J = 9.0 Hz, 1H, Ar-H), 7.76 (t, J = 4.5 Hz, 1H, Ar-H), 7.50 (d, J = 6.7 Hz, 2H, Ar-H), 7.46-7.30 (m, 7H, Ar-H), 7.25 (d, J = 1.5 Hz, 1H, Furan-H), 6.39 (s, 1H, Pyrrole-H), 6.10 (dd, J = 1.5, J = 3.0 Hz,

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1H, Furan-H) 5.63 (d, J = 3.7 Hz, 1H, Furan-H), 4.87 (s, 2H, CH2); 13C NMR

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(75 MHz, CDCl3): δ 47.3, 110.3, 111.2, 111.4, 121.7, 126.1, 126.3, 126.5, 126.6, 126.8, 127.7, 127.8, 127.9, 128.0, 128.2, 128.4, 129.6, 132.6, 133.3, 135.5, 136.8, 142.7, 145.6, 174.6; IR (KBr): υ 709, 802, 1221, 1602, 1726, 3054 cm-1; ESI-MS: m/z: 416 [M+Na]+; HRMS (ESI) calcd for C26H19O3NNa 416.1262 [M+Na]+, found: 416.1244.

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4.1.7 (Table 1): 2-(2-(furan-2-yl)-3-(naphthalene-1-yl)-5-phenyl-1H-pyrrol1-yl)acetic acid (4g). White solid, m.p: 145-147 °C; Yield: 84%; 1H NMR (300 MHz, CDCl3): δ 7.89

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(s, 1H, Ar-H), 7.86 (d, J = 8.9 Hz, 1H, Ar-H), 7.85-7.81 (m, 2H, Ar-H), 7.55 (d, J = 8.9 Hz, 1H, Furan-H), 7.50-7.47 (m, 3H, Ar-H), 7.31 (d, J = 7.9 Hz, 2H),

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7.24 (t, J = 7.9 Hz, 3H, Ar-H), 7.15 (t, J = 6.9 Hz, 1H, Ar-H), 6.50 (s, 1H, Pyrrole-H), 6.37 (t, J = 2.9 Hz, 1H, Furan-H ), 6.27 (d, J = 2.9 Hz, 1H, Furan-

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H), 4.70 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 47.9, 109.1, 111.0, 112.4, 123.6, 123.7, 125.3, 125.5, 125.7, 126.4, 127.1, 127.7, 127.8, 127.9, 128.7, 128.9, 129.0, 133.6, 141.3, 146.1, 175.3; IR (KBr): υ 761, 864, 1247, 1449, 1503, 1602, 1725, 2926, 3056 cm-1; HRMS (ESI) calcd for C26H20O3N

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394.1443 [M+H]+, found: 394.1440.

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4.1.8 (Table 1): 2-(2,3,5-triphenyl-1H-pyrrol-1-yl)acetic acid (4h). White solid, mp: 135-137 °C; Yield: 74%;1H NMR (300 MHz, CDCl3): δ 7.39

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(d, J = 7.7 Hz, 2H, Ar-H), 7.37 (t, J = 9.8 Hz, 1H, Ar-H), 7.34-7.26 (m, 7H, ArH), 7.06 (t, J = 8.0 Hz, 4H, Ar-H), 6.99 (t, J = 6.9 Hz, 1H, Ar-H), 6.47 (s, 1H, Pyrrole-H), 4.50 (s, 2H, CH2); 13C NMR (75MHz, CDCl3): δ 46.6, 109.5, 123.3, 125.3, 127.6, 128.0, 128.2, 128.6, 128.8, 129.0, 131.2, 132.2, 132.5, 132.7, 135.6, 135.7, 174.8; IR(KBr): υ 703, 777, 1008, 1223, 1346, 1478, 1722, 3054 cm-1; HRMS (ESI) calcd for C24H20O2N 354.1494 [M+H]+, found: 354.1503. 15

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4.1.9 (Table 1): 2-(3,5diphenyl-2-p-tolyl-1H-pyrrol-1-yl)acetic acid (4i). White solid, mp: 124-126 °C Yield: 86%; 1H NMR (300 MHz, CDCl3): δ 7.377.30, (m, 4H, Ar-H), 7.24 (t, J = 8.8 Hz, 6H, Ar-H), 7.19 (d, J = 6.9 Hz, 4H, Ar-

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H) 6.50 (s, 1H, Pyrrole-H), 4.51 (s, 2H), 2.41 (s, 3H, CH3); 13C NMR (75MHz, CDCl3): δ 21.2, 46.9, 109.3, 109.5, 123.8, 127.4, 128.6, 129.0, 129.3, 129.4, 129.5, 130.0, 130.9, 130.9, 133.0, 136.6, 136.9, 137.4, 139.9, 175.1; IR (KBr):

SC

υ 755, 824, 1223, 1601, 1706, 2822, 3028 cm-1; ESI-MS: m/z: 390 [M+Na]+.

M AN U

4.1.10 (Table 1): 2-(2-(4-bromophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic acid (4j).

White solid, mp: 194-196 °C; Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 7.49

TE D

(d, J = 8.3 Hz, 2H, Ar-H) 7.45-7.40 (m, 4H, Ar-H), 7.39-7.35 (m, 1H, Ar-H) 7.20 (t, J = 4.1 Hz, 6H, Ar-H), 7.13-7.09 (m, 1H, Ar-H) 6.45 (s, 1H, Pyrrole-H), 13

C NMR (75MHz, CDCl3): δ 46.7, 108.8, 121.5, 122.4,

EP

4.49 (s, 2H, CH2);

125.3, 127.1, 127.3, 128.1, 128.3, 128.6, 130.4, 131.5, 131.6, 132.3, 132.8,

AC C

135.2, 135.4, 170.4; IR (KBr): υ 743, 842, 1234, 1591, 1721, 2923, 3034 cm-1; HRMS (ESI) calcd for C24H18O2NNa 454.0414 [M+Na]+, found: 454.0416. 4.1.11 (Table 1): 2-(2-(4-chlorophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic acid (4k).

16

ACCEPTED MANUSCRIPT

White solid, mp:143-145 °C; Yield: 90%; 1H NMR: (300 MHz, CDCl3): δ 7.77-7.69 (m, 1H, Ar-H), 7.49 (d, J = 4.5 Hz, 1H, Ar-H), 7.44 (t, J = 8.3 Hz, 1H, Ar-H), 7.39-7.31 (m, 5H, Ar-H), 7.19 (d, J = 6.2 Hz, 5H, Ar-H), 7.10 (t, J = 13

C NMR (75

RI PT

6.2 Hz, 1H, Ar-H), 6.49 (s, 1H, Pyrrole-H), 4.43 (s, 2H, CH2);

MHz, CDCl3 +DMSO-d6): δ 46.7, 109.1, 122.8, 124.9, 125.7, 126.0, 126.3, 126.7, 127.0, 127.1, 127.4, 127.7, 128.4, 129.6, 130.6, 130.7, 131.8, 132.1,

SC

132.7, 133.2, 135.2, 135.2, 170.6; IR (KBr): υ 699, 768, 1043, 1204, 1452,

M AN U

1708, 3018 cm-1; ESI-MS: m/z: 387 [M+] 389 [M+2H]+.

4.2. General procedure for the preparation of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetamide derivatives

TE D

Compound 4 (1 mmol) was dissolved in freshly dry dichloromethane under nitrogen atmosphere. Then HOBt (1.1 mmol), EDC.HCl (1.1 mmol) were added to the above solution. The resulting mixture was stirred for 5 min, and then (R4)

(1.2

mmol)

EP

amine

was

added

slowly

followed

by

N,N-

AC C

diisopropylethylamine (DIPEA) (1.2 mmol). The mixture was allowed to stir for 3h at room temperature. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (10-15 mL) and extracted with dichloromethane. The organic layer was collected and dried over anhydrous Na2SO4 . The solvent was removed under reduced pressure and the resultant crude material was purified by column chromatography. 17

ACCEPTED MANUSCRIPT

4.2.1 (Table 2): N-(benzo[d]thiazol-2yl)-2-(furan-2-yl)-3,5-diphenyl-1Hpyrrol -1-yl)acetamide (5a). White solid, m.p: 113-115 ºC; Yield: 78%; 1H NMR (300 MHz, CDCl3): δ 7.78

RI PT

(d, J = 7.5 Hz, 1H, Ar-H) 7.53 (d, J = 8.3 Hz, 1H, Ar-H), 7.45-7.17 (m, 13H, Ar-H, Furan-H), 6.52 (s, 1H, Pyrrole-H), 6.34 (t, J = 3.0 Hz, 1H, Furan-H ), 6.28 (d, J = 3.0 Hz, 1H, Furan-H), 4.75 (s, 2H, CH2);

13

C NMR (75 MHz,

SC

CDCl3): δ 49.4, 110.9, 111.3, 112.0, 120.8, 121.4, 124.2, 126.4, 127.6, 127.9,

M AN U

128.3, 128.9, 131.5, 132.0, 135.0, 137.1, 143.1, 144.9, 147.8, 157.4, 167.5; IR (KBr): υ 758, 1271, 1545, 1703, 2924, 3060, 3351 cm-1; ESI-MS: m/z: 476 [M+H]+, 498 [M+Na]+; HRMS (ESI) calcd for C29H21N3O2NaS, 498.1252

4.2.2

(Table

2):

TE D

[M+Na]+, found: 498.1258.

N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(furan-2-yl)-3,5-

dipheny l-1H-pyrrol-1-yl)acetamide (5b).

EP

White solid, m.p: 236-238 °C; Yield: 81%; 1H NMR (300 MHz, CDCl3) δ 8.03

AC C

(d, J = 7.5 Hz, 1H, Ar-H),7.80 (d, J = 7.7 Hz, 1H, Ar-H), 7.75 (d, J = 3.0 Hz, 1H, Ar-H), 7.56 (d, J = 6.7 Hz, 2H, Ar-H), 7.45-7.27 (m, 5H, Ar-H), 7.01 (d, J = 3.3 Hz, 1H, Furan-H), 6.44 (s, 1H, Pyrrole-H), 5.99 (t, J = 3.0 Hz, 1H, FuranH), 5.65 (d, J = 3.0 Hz, 1H, Furan-H), 5.21. (s, 2H, CH2), 3.02 (qt, 2H, CH2), 1.40 (t, J = 7.5 Hz, 3H, CH3);13C NMR (75 MHz, CDCl3): δ 13.6, 22.5, 47.8, 108.6, 111.2, 111.7, 121.0, 125.3, 125.7, 126.7, 127.6, 128.1, 128.4, 128.6, 18

ACCEPTED MANUSCRIPT

131.8, 135.0, 136.4, 143.6, 144.6, 157.5. 165.6. 166.9; IR (KBr): υ 761, 1307, 1570, 1707, 2872, 3055 cm-1; ESI-MS: m/z: 477 [M+Na]+; HRMS (ESI) calcd for C26H22N4O2NaS, 477.1361 [M+Na]+, found: 477.1369. (Table

2):

N-benzyl-2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-

RI PT

4.2.3

yl)aceta mide (5c).

SC

White solid, m.p: 178-180 °C; Yield: 80%; 1H NMR (300 MHz, CDCl3): δ 7.43-7.34 (m, 6H, Ar-H),7.32-7.25 (m, 7H, Ar-H), 7.22-7.16 (m, 3H, Ar-H),

M AN U

6.51 (s, 1H, Pyrrole-H), 6.39 (dd, J = 1.8, 3.3 Hz, 1H, Furan-H), 6.25 (d, J = 3.0 Hz, 1H, Furan-H), 5.99-5.92. (m, 1H, Ar-H), 4.63 (s, 2H, CH2), 4.44 (d, J = 7.5 Hz, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 43.2, 49.3, 110.3, 111.1, 111.9,

TE D

120.2, 121.3, 125.1, 126.2, 127.2, 127.4, 127.5, 127.6, 128.0, 128.2, 128.5, 128.7, 131.6, 135.0, 136.9, 137.6, 142.9, 144.9, 168.7; IR (KBr): υ 759, 1248, 1557, 1661, 2924, 3064 cm-1; ESI-MS: m/z: 433 [M+H]+; HRMS (ESI) calcd

EP

for C29H25N2O2, 433.1916 [M+ H]+, found: 433.1931.

AC C

4.2.4 (Table 2): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-yl)-N-(pyridin2-yl)acetamide (5d).

White solid, m.p: 118-120 °C; Yield:74%; 1H NMR (300 MHz, CDCl3): δ 8.18 (d, J = 6.7 Hz, 2H, Pyridine-H), 7.66 (t, J = 7.5 Hz, 1H, Ar-H), 7.45 (d, J = 7.5 Hz, 3H, Ar-H), 7.38 (t, J = 7.5 Hz, 2H, Pyridine-H), 7.35-7.29 (m, 3H, Ar-H, Furan-H), 7.25 (t, J = 6.7 Hz, 2H, Ar-H), 7.16 (t, J = 7.5 Hz, 1H, Ar-H), 7.00 (t, 19

ACCEPTED MANUSCRIPT

J = 6.0 Hz, 1H, Ar-H), 6.54 (s, 1H, Pyrrole-H), 6.35 (t, J = 3.7 Hz, 1H, FuranH), 6.29 (d, J = 3.7 Hz, 1H, Furan-H). 4.65 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 49.9, 110.6, 111.2, 112.0, 114.0, 120.2, 126.2, 127.7, 128.0, 128.2,

RI PT

128.8, 128.9, 131.7, 135,1, 137.0, 138.3, 143.0, 145.0, 147.8, 150.5, 167.4; IR (KBr): υ 778 , 1306, 1447, 1571, 1712, 2926, 3054 cm-1; ESI-MS: m/z: 420 [M+H]+, HRMS (ESI) calcd for

C27H22N3O2, 420.1712 [M+H]+, found:

SC

420.1707.

1H-pyrrol-1-yl)acetamide (5e).

M AN U

4.2.5 (Table 2): N-(2-(1H-indol-3-yl)ethyl)-2-(2-(furan-2-yl)-3,5-diphenyl-

Orange solid, m.p: 105-107 °C; Yield: 88%; 1H NMR (300 MHz, CDCl3): δ

TE D

7.77 (s, 1H, Indole-H), 7.48 (d, J = 7.5 Hz, 1H, Ar-H), 7.28 (t, J = 3.1 Hz, 6H, Ar-H), 7.21 (d, J = 7.3 Hz, 2H, Ar-H), 7.15 (t, J = 8.1 Hz, 3H, Ar-H), 7.03 (t, J = 7.9 Hz, 1H, Ar-H), 6.71 (d, J = 1.5 Hz, 1H, Ar-H), 6.41, (s, 1H, Pyrrole-H),

EP

6.29. (t, J = 1.7 Hz, 1H, Furan-H), 6.00 (d, J = 3.0 Hz, 1H, Furan-H), 5.60 (t, J

AC C

= 4.3 Hz, 1H, Furan-H). 4.42 (s, 2H, CH2), 3.51 (qt, 2H, CH2), 2.86 (t, J = 6.4 Hz, 2H, CH2);

13

C NMR (75 MHz, CDCl3): δ 24.8, 38.8, 49.2, 109.8, 111.1,

111.2, 111.9, 112.0, 118.5, 119.3, 120.9, 122.2, 126.3, 126.8, 126.9, 127.3, 127.9, 128.4, 128.7, 128.7, 131.5, 135.1, 136.4, 136.7, 143.0, 144.6, 168.6; IR (KBr): υ 698, 1228, 1526, 1663, 2925, 3025, 3296 cm-1; ESI-MS: m/z: 486

20

ACCEPTED MANUSCRIPT

[M+H]+, 508 [M+Na]+; HRMS (ESI) calcd for C32H27N3O2Na, 508.2000 [M+Na]+, found: 508.1993. 4.2.6 (Table 2): N-(benzo[d]thiazol-2yl)-2-(2,3,5-triphenyl-1H-pyrrol-1-yl)

RI PT

ac etamide (5f).

White solid, m.p: 129-131 °C; Yield: 76%; 1H NMR (300 MHz, CDCl3): δ 7.76

SC

(d J = 7.9 Hz, 1H, Ar-H), 7.49 (t, J = 7.9 Hz, 3H, Ar-H), 7.40-7.25 (m, 11H, ArH), 7.18 (t, J = 7.1Hz, 2H, Ar-H), 7.14 (d, J = 7.5 Hz, 1H, Ar-H), 7.07 (t, J =

M AN U

6.7 Hz 1H, Ar-H), 6.57 (s, 1H, Pyrrole-H), 4.67 (s, 2H, CH2);

13

C NMR (75

MHz, CDCl3): δ 48.7, 110.5, 120.6, 121.4, 124.2, 124.3, 125.6, 126.4, 127.7, 128.0, 128.1, 128.4, 128.9, 129.1, 131.9, 132.1, 132.2, 135.3, 135.7, 147.7,

TE D

157.8, 157.9, 167.5; IR (KBr): υ 756, 1271, 1555, 1601, 1709, 2925, 3057 cm-1; ESI-MS: m/z: 486 [M+H]+, 508 [M+Na]+; HRMS (ESI) calcd for C31H24N3OS,

4.2.7

(Table

EP

486.1640 [M+H]+, found: 486.1655. 2):

N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2,3,5-triphenyl-1H-

AC C

pyrrol-1-yl)acetamide (5g).

White solid, m.p: 182-184 °C; Yield: 82%; 1H NMR (300 MHz, CDCl3): δ 7.50 (d, J = 6.9 Hz, 2H, Ar-H), 7.39 (t, J = 7.3 Hz, 1H, Ar-H), 7.30 (t, J = 6.6 Hz, 3H, Ar-H ), 7.25 (d, J = 8.3 Hz, 1H, Ar-H), 7.21 (d, J = 7.5 Hz, 1H, Ar-H), 7.17-7.08 (m, 6H, Ar-H ), 7.02 (t, J = 6.9 Hz, 1H, Ar-H), 6.52 (s, 1H, PyrroleH), 4.86 (s, 2H, CH2), 2.99 (qt, 2H, CH2), 1.40 (t, J = 7.5 Hz, 3H, CH3); 21

13

C

ACCEPTED MANUSCRIPT

NMR (75 MHz, CDCl3): δ 13.7, 22.6, 47.7, 108.8, 122.1, 125.2, 127.0, 127.4, 128.1, 128.3, 128.4, 128.7, 130.9, 132.0, 132.2, 132.4, 135.2, 135.6, 157.6, 165,8, 167.4; IR (KBr): υ 754, 1303, 1560, 1717, 2922, 3050 cm-1; ESI-MS:

RI PT

m/z: 465 [M+H]+; HRMS (ESI) calcd for C28H25ON4S, 465.17592 [M+H]+, found: 465.17436. (Table

2):

N-(pyridin-2-yl)-2-(2,3,5-triphenyl-1H-pyrrol-1-

SC

4.2.8

yl)acetamide (5h).

M AN U

White solid, mp: 103-105 °C Yield: 75%; 1H NMR (300 MHz, CDCl3): δ 8.12 (t J=8.6Hz,1H, Ar-H), 7.68 (t, J = 7.3 Hz, 1H, Ar-H), 7.48 (d, J = 6.6 Hz, 1H, Ar-H), 7.41 (t, J = 6.6 Hz, 1H, Ar-H), 7.37-7.26 (m, 9H, Ar-H), 7.15 (t, J = 8.6

TE D

Hz, 4H, Ar-H), 7.06 (d, J = 6.7 Hz, 1H, Ar-H), 7.01 (t, J = 7.3 Hz, 1H, Ar-H), 6.57 (s, 1H, Pyrrole-H), 4.59 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 48.7, 110.5, 120.6, 121.4, 124.2, 124.3, 125.6, 126.4, 127.7, 128.0, 128.1, 128.4,

EP

128.8, 128.9, 129.1, 131.0, 131.9, 132.1, 132.2, 135.3, 135.7, 147.7, 157.8,

AC C

167.5; IR (KBr): υ 755, 1191, 1303, 1561, 1716, 2934, 3050 cm-1. ESI-MS: m/z: 430 [M+H]+, 452[M+Na]+; HRMS (ESI) calcd for C29H24N3O, 430.1919 [M+H]+, found: 430.1900. 4.2.9 (Table 2): N-(benzo[d]thiazol-2-yl)-2-(2,3-di(furan-2-yl)-5-phenyl-1Hpyrrol-1-yl)acetamide (5i).

22

ACCEPTED MANUSCRIPT

Brown solid, m.p: 112-114 °C; Yield: 79%, 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H, Furan-H), 7.70 (d, J = 7.5 Hz, 1H, Furan-H), 7.50-7.28 (m, 9H, Ar-H), 6.68 (s, 1H, Pyrrole-H), 6.62 (d, J = 3.7 Hz, 1H, Furan-H), 6.47 (t, J

1H, Furan-H), 4.76 (s 2H, CH2);

13

RI PT

= 3.0 Hz, 1H, Furan-H), 6.38 (t, J = 3.0 Hz, 1H, Furan-H), 6.20 (d, J = 3.0 Hz, C NMR (75 MHz, CDCl3): δ 49.3, 105.1,

109.0, 111.0, 111.3, 112.2, 118.2, 120.4, 120.9, 121.4, 124.2, 126.4, 126.6,

SC

128.4, 128.9, 129.0, 131.2, 137.1, 140.8, 143.3, 144.2, 147.9, 149.3, 157.2,

M AN U

167.2; IR (KBr): υ 761, 1306, 1567, 1709, 2934, 3050 cm-1; ESI-MS: m/z: 465 [M+H]+.

4.2.10 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2,3-di(furan-2-yl)-5-

TE D

phenyl -1H-pyrrol-1-yl)acetamide (5j).

Brown solid, mp: 117-119 °C Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 7.47 (d, J = 6.7 Hz, 1H, Furan-H), 7.37-7.26 (m, 5H, Ar-H), 6.77 (t, J = 3.5 Hz, 1H,

EP

Furan-H) 6.58 (s, 1H, Pyrrole-H) 6.51 (d, J = 3.1 Hz, 1H, Furon-H), 6.28 (t, J =

AC C

2.2 Hz, 2H, Furan-H), 6.05 (d, J= 3.0 Hz, 1H Furan-H), 4.92 (s, 2H, CH2), 3.00 (qt, 2H, CH2), 1.39 (t, J = 7.5 Hz, 3H, CH3);

13

C NMR (75 MHz, CDCl3): δ

13.6, 22.5, 48.5, 109.4, 110.9, 111.5, 122.8, 123.3, 125.3, 125.5, 125.7, 126.9, 127.4, 127.6, 127.9, 128.4, 128.7, 131.7, 131.8, 133.2, 133.6, 136.1, 142.5, 145.2, 165.6, 167.2; IR (KBr): υ 702, 1214, 1338, 1603, 1718, 2926 cm-1; ESI-

23

ACCEPTED MANUSCRIPT

MS: m/z: 445 [M+H]+; HRMS (ESI) calcd for C24H21N4O3 S, 445.1328 [M+H]+, found: 445.1329. 4.2.11

(Table

2):

N-(benzo[d]thiazol-2-yl)-2-(2-(4-bromophenyl)-3,5-

RI PT

diphenyl-1H-pyrrol-1-yl) acetamide (5k).

White solid, m.p: 111-113 °C; Yield:80%, 1H NMR (300 MHz, CDCl3): δ 7.79

SC

(d, J = 5.2 Hz, 1H, Ar-H), 7.52 (d, J = 8.3 Hz, 1H, Ar-H) 7.45 (t, J = 8.3 Hz, 4H, Ar-H), 7.36 (t, J = 6.7 Hz, 2H, Ar-H), 7.32-7.29 (m, 2H, Ar-H), 7.25-7.17

2H, CH2);

13

M AN U

(m, 7H, Ar-H), 7.12 (t, J = 4.5 Hz, 1H, Ar-H) 6.62 (s, 1H, Pyrrole-H), 4.65 (s, C NMR (75 MHz, CDCl3): δ 48.7, 110.9, 120.6, 121.5, 122.8,

124.3, 125.9, 126.5, 127.8, 128.1, 128.2, 128.9, 129.0, 130.8, 131.9, 132.2,

TE D

132.6, 135.0, 136.2, 147.6, 157.7, 167.3; IR (KBr): υ 757, 1270, 1553, 1709, 2926, 3057 cm-1; ESI-MS: m/z: 564 [M]+, HRMS (ESI) calcd for

EP

C31H23ON3BrS, [M]+, 564.07397 found:564.07579. 4.2.12 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(4-bromophenyl)-3,5-

AC C

diphenyl-1H-pyrrol-1-yl) acetamide (5l). White solid, m.p: 226-228 °C; Yield: 74%; 1H NMR (300 MHz, CDCl3): δ 7.44 (d, J = 7.9 Hz, 4H, Ar-H), 7.37 (t, J = 6.9 Hz, 2H, Ar-H), 7.29 (t, J = 6.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.9 Hz, 2H, Ar-H), 7.16 (d, J = 4.9 Hz, 4H, Ar-H), 7.07 (t, J = 4.9 Hz, 1H, Ar-H), 6.44 (s, 1H, Pyrrole-H), 4.61 (s, 2H, CH2), 3.02 (qt, 2H, CH2), 1.41 (t, J = 7.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 13.6, 24

ACCEPTED MANUSCRIPT

22.6, 47.7, 106.4, 109.0, 109.7, 119.7, 121.6, 122.6, 125.3, 127.1, 127.4, 128.2, 128.4, 128.6, 129.0, 130.6, 131.4, 131.7, 132.2, 132.9, 135.4, 135.6, 142.7, 157.4, 165.7, 167.2; IR (KBr): υ 758, 1131, 1574, 1709, 2924, 3051 cm-1; ESI-

RI PT

MS: m/z: 545 [M+2H]+; HRMS (ESI) calcd for C28H25BrN4OS, 545.0826 [M+2H]+, found: 545.07805.

SC

4.2.13 (Table 2): 2-(2-(4-bromophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)-N(pyri din-2-yl)acetamide (5m).

M AN U

White solid, m.p: 175-177 °C; Yield: 69%; 1H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 4.1 Hz, 1H, Pyridine-H ), 8.05 (d, J = 8.1 Hz, 1H, Pyridine-H), 7.64 (t, J = 8.3 Hz, 1H, Pyridine-H), 7.46 (d, J = 7.9 Hz, 3H, Ar-H), 7.39 (t, J = 6.9 Hz,

TE D

1H, Ar-H), 7.31 (t, J = 7.1 Hz, 1H, Ar-H), 7.25-7.15 (m, 8H, Ar-H), 7.11 (t, J = 7.9 Hz, 1H, Pyridine-H), 7.00 (t, J = 6.2 Hz, 1H, Ar-H), 6.59 (s, 1H, Pyrrole-H), 4.58 (s, 2H, CH2);

13

C NMR (75 MHz, CDCl3): δ 48.2, 108.7, 113.4, 119.6,

EP

121.5, 122.3, 125.2, 127.0, 127.3, 128.1, 128.3, 128.5, 130.6, 131.5, 132.3,

AC C

132.9, 135.5, 138.2, 147.9, 151.1, 167.5; IR (KBr): υ 756, 1300, 1482, 1689, 2941, 3294 cm-1; ESI-MS: m/z: 508 [M]+, 510 [M+2H]+; HRMS (ESI) calcd for C29H24BrN3O 510.1908, found: 510.1203. 4.2.14 (Table 2): N-(benzo[d]thiazol-2-yl)-2-(2-(furan-2-yl)-5-(naphthalen2-yl)-3-phenyl-1H-pyrrol-1-yl)acetamide (5n).

25

ACCEPTED MANUSCRIPT

White solid, m.p:122-124 °C; Yield: 79%; 1H NMR (300 MHz, CDCl3): δ 7.90 (d J = 8.3 Hz, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.85-7.79 (m, 3H, Ar-H), 7.72 (d, J = 7.5 Hz, 1H, Ar-H), 7.55 (dd, J = 6.7, 8.3 Hz, 1H, Furan-H), 7.51-7.47 (m,

RI PT

2H, Ar-H), 7.45 (t, J = 3.0 Hz, 2H, Ar-H), 7.40 (d, J = 7.1 Hz, 2H, Ar-H), 7.377.30 (m, 3H, Ar-H), 7.24 (t, J = 6.7 Hz, 1H, Ar-H), 6.68 (s, 1H, Pyrrole-H), 6.37 (t, J = 3.0 Hz, 1H, Furan-H), 6.33 (d, J = 3.0 Hz, 1H, Furan-H), 4.89 (s,

SC

2H, CH2);13C NMR (75 MHz, CDCl3): δ 49.5, 111.4, 112.0, 120.9, 121.4,

M AN U

121.6, 124.2, 126.4, 126.4, 126.5, 126.6, 127.6, 127.8, 127.9, 128.0, 128.3, 128.7, 132.7, 135.0, 143.1, 157.4, 167.4; IR (KBr): υ 758, 1259, 1576, 1710, 2935, 3051 cm-1; ESI-MS: m/z: 548 [M+Na]+. HRMS (ESI) calcd for C33H23N3O2NaS, 548.1408 [M+Na]+, found: 548.2970. (Table

2):

N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(furan-2-yl)-5-

TE D

4.2.15

(naphth alen-2-yl)-3-phenyl-1H-pyrrol-1-yl)acetamide (5o).

EP

White solid, mp: 153-155 °C; Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 7.93

AC C

(s, 1H, Ar-H), 7.89-7.74 (m, 3H, Ar-H), 7.59 (d, J = 8.3 Hz, 1H, Ar-H), 7.497.41 (m, 3H, Ar-H), 7.25 (t, J = 6.9 Hz, 4H, Ar-H), 7.14 (t, J = 6.6 Hz, 1 H, ArH), 6.54 (s, 1H, Pyrrole-H), 6.42 (t, J = 3.0 Hz,1H, Furan-H), 6.35 (d, J = 3.2 Hz, 1H, Furan-H), 4.81 (s, 2H, CH2), 3.04 (qt, 2H, CH2), 1.42 (t, J = 7.5 Hz, 3H, CH3);

13

C NMR (75 MHz, CDCl3): δ 13.5, 22.5, 47.9, 109.2, 111.2, 111.8,

121.3, 125.4, 125.6, 125.8, 126.2, 126.4, 126.4, 126.7, 127.0, 127.4, 127.8, 26

ACCEPTED MANUSCRIPT

128.1, 129.0, 129.3, 132.0, 132.7, 135.0, 136.4, 143.7, 144.6, 166.9; IR (KBr): υ 756, 1215, 1340, 1605, 1720, 2926 cm-1; ESI-MS: m/z: 505 [M+H]+; HRMS (ESI) calcd for C30H25N4O2S, 505.16927 [M+H]+, found: 505.16940.

RI PT

4.2.16 (Table 2): N-benzyl-2-(2-(furan-2-yl)-5-(naphthalen-2-yl)-3-phenyl1H-pyrrol-1-yl)acetamide (5p).

SC

White solid, m.p: 147-149 °C; Yield: 74%; 1H NMR (300 MHz, CDCl3): δ 7.81 (t, J = 8.3 Hz, 2H, Ar-H), 7.77 (s, 1H) 7.71 (d, J = 3.0 Hz, 1H, Ar-H), 7.48 (t, J

M AN U

= 3.7 Hz, 3H, Ar-H), 7.38 (d, J = 1.5 Hz, 1H, Furan-H), 7.25-7.20 (m, 7H, Ar-H ), 7.19-7.12 (m, 2H, Ar-H ), 6.62 (s, 1H, Pyrrole-H ), 6.38 (dd, J = 2.2, 5.2 Hz, 1H, Furan-H), 6.22 (d, J = 3.7 Hz, 1H, Furan-H), 6.06 (t, J = 6.0 Hz, 1H, Ar-H),

TE D

4.70 (s, 2H, CH2), 4.45 (d, J = 6.0 Hz, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 43.3, 49.6, 110.8, 111.2, 112.0, 121.7, 126.3, 126.4, 126.5, 127.4, 127.6, 128.1, 128.3, 128.5, 129.0, 132.6, 133.2, 135.1, 136.9, 137.6, 143.0, 144.9, 168.7; IR

EP

(KBr): υ 761, 1250, 1543, 1671, 2920, 3062 cm-1; ESI-MS: m/z: 483 [M+H]+.

AC C

4.2.17 (Table 2): N-(benzo[d]thiazol-2-(2-(furan-2-yl)-3-(naphthalen-2-yl)5-phenyl-1H-pyrrol-1-yl)acetamide (5q). White solid, m.p: 119-121°C; Yield: 78%; 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 7.5 Hz, 1H, Ar-H ), 7.55 (d, J = 7.5 Hz, 1H, Ar-H ), 7.45-7.34 (m, 11H, Ar-H), 7.29 (d, J = 6.7 Hz, 2H, Ar-H ), 6.63 (s, 1H, Pyrrole-H), 6.58 (d, J = 3.0 Hz, 1H, Furan-H), 6.43 (t, J = 3.0 Hz, 1H, Ar-H), 6.31 (t, J = 3.0 Hz, 1H, Furan27

ACCEPTED MANUSCRIPT

H), 6.11 (d, J = 3.7 Hz, 1H, Furan-H), 4.71 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 50.2, 110.1, 111.2, 113.7, 120.9, 121.4, 124.2, 125.4, 125.6, 125.9, 126.2, 126.4, 127.5, 127.9, 128.1, 128.2, 128.9, 131.4, 132.3, 133.4, 133.7,

RI PT

136.9, 142.0, 148.1, 157.3, 157.4, 167.8; IR (KBr): υ 758, 1270, 1546, 1708, 2923, 3056 cm-1; ESI-MS: m/z: 526 [M+H]+, HRMS (ESI) calcd for

SC

C33H24N3O2S, 526.1583 [M+H]+, found: 526.1579.

4.2.18 (Table 2): N-(5-ethylthiazol-2-yl)-2-(2-(furan-2-yl)-3-(naphthalen-2-

M AN U

yl)-5-phenyl-1H-pyrrol-1-yl)acetamide (5r).

White solid, m.p: 161-163°C; Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J = 7.5 Hz, 1H, Ar-H), 7.80 (d, J = 7.5 Hz, 1H, Ar-H), 7.74 (d, J = 3.0 Hz,

TE D

1H, Ar-H ), 7.56 (d, J = 6.7 Hz, 2H, Ar-H), 7.45-7.27 (m, 7H, Ar-H), 7.00 (d, J = 1.5 Hz, 1H, Furan-H), 6.45 (s, 1H, Pyrrole-H), 5.98 (t, J = 3.0 Hz, 1H, FuranH), 5.65. (d, J = 3.0 Hz, 1H, Furan-H), 5.20 (s, 2H, CH2), 3.01 (qt, 2H, CH2),

EP

1.40 (t, J = 7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 12.1, 21.3, 46.6,

AC C

107.6, 109.5, 110.0, 119.9, 124.0, 124.1, 124.5, 124.8, 124.9, 125.3, 125.6, 125.8, 126.2, 126.5, 127.8, 130.6, 131.3, 133.5, 135.0, 141.4, 141.5, 143.3, 156.2, 164.1, 165.7; IR (KBr): υ 752, 1273, 1550, 1698, 2921, 3056 cm-1; ESIMS: m/z: 505 [M+H]+, 527 [M+Na]+. 5. Acknowledgments

28

ACCEPTED MANUSCRIPT

P.L.R. thankful to UGC, New Delhi, India for the financial support in the form of fellowships and also thankful to Dr V.J. Rao for his support and encouragement.

RI PT

6. References and notes

[1] Skrahina, A.; Hurevich, H.; Zalutskaya, A.; Sahalchyk, E.; Astrauko, A.;

SC

Hoffner, S.; Rusovich, V.; Dadu, A.; Colombani, P.D.; Dara, M.; Gemert, W.V.; Zignol. M. Bull World Health Organ 2013, 91, 36.

M AN U

[2] Hafizi, H.; Aliko, A.; Sharra, E.; Fico, A.; Migliori, G.B.; Castiglia, P.; Sotgiu, G. J Infect Dev Ctries 2014, 8, 310.

[3] World Health Organization (2012) Global tuberculosis report 2012.

TE D

WHO/HTM/TB/2012.6. Geneva: WHO.

[4] Espinal, M. A. The Global Situation of MDR-TB. Tuberculosis 2003, 83, 44.

EP

[5] Frieden, T. R.; Munsiff, S. S. The DOTS Strategy for Controlling the

AC C

Global Tuberculosis Epidemic. Clin. Chest Med. 2005, 26, 197. [6] Biaya, M.; Porretta, G. C.; Poce, G.; Supino, S.; Deidda, D.; Pompei, R.; Molicotti, P.; Manetti, F.; Botta. M. J. Med. Chem. 2008, 51, 3644. [7] Idhayadhulla, A.; Kumar, R. S.; Nasser, A. J. A. J. Mex. Chem. Soc. 2011, 55, 218. [8] Biaya, M.; Porretta, G. C.; Poce, G.; De Logu, A.; Meleddu, R.; De Rossi, E.; Manetti, F.; Botta. M. Eur. J. Med. Chem. 2009, 51, 4734. 29

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[9] Biaya, M.; Porretta, G. C.; Poce, G.; Supino, S.; Deidda, D.; Pompei, R.; Molicotti, P.; Manetti, F.; Botta, M. J. Med. Chem. 2006, 49, 4946-4952. [10] Singh, A. K.; Mishra, G.; Jyoti, K. J. Appl. Pharma. Sci. 2011, 1, 44.

RI PT

[11] Idhayadhulla, A.; Kumar, R. S.; Nasser, A. J. A.; Manilal, A. Der Pharma Chemica 2011, 3, 210.

Bioorg. Med. Chem. Lett. 2010, 20, 7507.

SC

[12] Reddy, B. V. S.; Reddy, M. R.; Madan, Ch.; Kumar, K. P.; Rao, M. S.

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[13] Reddy, P. L.; Kumar, K. P.; Satyanarayana, S.; Narender, R.; Reddy, B. V. S. Tetrahedron Lett. 2012, 53, 1546.

[14] Cole, D. C.; Stock, J. R.; Chopra, R.; Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B. L.; Hu, Y.; Jacobsen, S.; Jennings, L. D.; Jin, G.; Lohse,

TE D

P. A.; Malamas, M. S.; Manas, E. S.; Moore, W. J.; O’Donnell, M.-M.; Olland, A. M.; Robichaud, A. J.; Svenson, K.; Wu, J. J.; Wagnerd, E.;

EP

Bardd, J. Bioorg. Med. Chem. Lett. 2008, 18, 1063. [15] Nicolaou, L.; Demopoulos, V. J. J. Med. Chem. 2003, 46, 417.

AC C

[16] Faghih, R.; Gopalakrishnan, S. M.; Gronlien, J. H.; Malysz, J.; Briggs, C. A.; Wetterstrand, C.; Ween, H.; Curtis, M. P.; Sarris, K. A.; Gfesser, G. A.; El-Kouhen, R.; Robb, H. M.; Radek, R.J.; Marsh, K. C.; Bunnelle, W. H.; Gopalakrishnan, M. J. Med. Chem. 2009, 52, 3377. [17] Ullrich, T.; Ghobrial, M.; Weigand, K. Synthetic Communications. 2007, 37, 1109. 30

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[18] Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447. [19] Chaturvedi, V.; Dwivedi, N.; Tripathi, R. P.; Sinha, S. J. Gen. Appl. Microbiol. 2007, 53, 333.

RI PT

[20] Altaf, M.; Miller, C. H.; Bellows, D. S.; O’Toole, R. Tuberculosis 2010, 90, 333.

[21] Senthilkumar, P.; Dinakaran, M.; Yogeeswari, P.; China, A.; Nagaraja,

SC

V.; Sriram, D. Biomedicine & Pharmacotherapy 2009, 63, 27.

[23]

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[22] Pfaller, M. A.; Barry, A. L. J. Clin. Microbiol. 1994, 32, 1992. (a) Scott, R.S.W.; Franzblau, G.; McLaughlin, J.C.; Torres, P.; Madico,

G.; Hernandez, A.; Michelle, T.; Degnan, M. B.; Cook, V.K.; Quenzer, R. M.; Ferguson, and Gilman, R. H.; Rapid, Low-Technology MIC

TE D

Determination with Clinical Mycobacterium Tuberculosis Isolates busing the Microplate Alamar Blue Assay, Journal of Clinical Microbiology, 1998, 36,

EP

362-366.

[24] Gerlier, D.; Thomasset, N.; Use of MTT colorimetric assay to measure

AC C

cell activation, Journal of Immunological Methods, 1986, 94, 57-63. [25] Orme, Ian.; Secrist, J.; Anathan, S.; Kwong, C.; Maddry, J.; Reynolds, R.; Poffenberger, A.; Michael, M.; Miller, L.; Krahenbuh, J.; Adams, L.; Biswas, A.; Franzblau, S.; Rouse, D.; NWinfield, D.; Brooks, J.; Antimicrobial Agents and Chemotherapy, 2001, 45, 943–1946.

31

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Figure, Table, and Scheme Captions Fig.1. Pyrrole (a-d), benzthiazole (e) and thiadiazole (f,g) containing antitubercular agents.

RI PT

Fig 2. Design the molecules based on TB active Compounds.

Table 1. Synthesis of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives.

SC

Table 2. Synthesis of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetamide derivatives.

M AN U

Table 3. Anti TB evaluation of 4a-4k against M. tuberculosis H37RV, and Antibacterial activity against Pseudomonas aeruginosa. Table 4. Anti TB evaluation of 5a-5r against M. smegmatis, M. tuberculosis H37RV, and Antibacterial activity against Pseudomonas aeruginosa. Table 5. Percentage (%) cell inhibition and selectivity index (SI) values of

HEK-293Tcell line.

TE D

tetrasubstituted pyrrolyl-N-acetic acid and acetamides (4a-4k & 5a-5r) against

AC C

EP

Scheme 1. Synthesis of title compounds 3, 4 and 5.

32

ACCEPTED MANUSCRIPT N O

N

N

N

N

N

CF 3

O N

a

O Cl

N

BM212

LL- 3858

SH

c

b

d

N N N NH

NH

O2N

N N

S

e

f

O

N N

S

M AN U

N

S

Cl

SC

N

O

RI PT

Cl

N N

N HN

N

Cl

S

S

O

g

Fig.1 Pyrrole (a-d), benzthiazole (e) and thiadiazole (f,g) containing

AC C

EP

TE D

antitubercular

33

agents.

ACCEPTED MANUSCRIPT N

N

N

N

N HN

N

CF 3

O

Cl

N

Cl

RI PT

N HO

N N

Br

N N

N

NH O

O N

N

H N O

O

O

N

Cl O2N

HN

H N

S

O

SC

S

S

N

N

M AN U

N

Cl

S

NH

N N

O

AC C

EP

TE D

Fig 2. Design the molecules based on TB active compounds.

34

O

ACCEPTED MANUSCRIPT

Table 1. Synthesis of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives Entry

Amino acid (2)

1,4-Diketone (1)

a

OH

O O

Yield (%)

O

NH2

O

4a

Product ( 3)

b

Time (h)

95

N

12

OH

O

NH2

O

O

4b

OH

O O

N

69 OH

O O

NH2 OH

O

4c

O

61

N

O O O

OH

O

O NH2 O

4d

24

O

OH

79

N

O

12

OH

M AN U

O O

24

SC

O

RI PT

O

O

O

O

NH2

4e

O

OH

O

O

O O

75

24

85

12

84

12

74

24

86

12

83

12

90

12

N

OH

O

NH2

O

4f

OH

O

O

O O

N

OH

4g

TE D

O

NH2

O

OH

O O

OH

O

O

EP

NH2 OH

4h

N

O

O O

AC C

O N

OH O

NH2

4i

OH O O

N OH

O O

NH2

4j

Br

OH

O O

N OH

O

Br

O

NH2 Cl

4k O O

OH

N

Cl OH

O O

a

All products were characterized by NMR, IR and mass spectroscopy. b Yield refers to pure products after chromatography.

35

ACCEPTED MANUSCRIPT

Table 2. Synthesis of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetamide derivatives Entry

R1

R2

5a

Ph

Ph

R3

R4

O

S

Yield (%)b

78

N 5b

Ph

O

Ph

S 81

5c

Ph

Ph

5d

Ph

Ph

O

80

O

74

N O 5e

Ph

RI PT

N N

Ph

88

5f

Ph

Ph

SC

N H

S

Ph

76

5g

Ph

Ph

M AN U

N

S

Ph

82

N N

5h

Ph

Ph

Ph

75

N

O 5i

Ph

O

S

79

N

O 5j

Ph

O

S

83

5k

Ph

Ph

EP

5l

TE D

N N

5m

Ph

AC C

5n

5o

5p

5q

Ph

Br

N 80 S

Ph

Br

S 74 N N

Ph

Br

69 N

O

Ph

N 79 S

O

Ph

S 83 N N

O

Ph

74 O

Ph

N 78 S

5r

O

Ph

S N N

36

83

ACCEPTED MANUSCRIPT

Table 3. Anti TB evaluation of 4a-4k against M. tuberculosis H37RV, and Antibacterial activity against Pseudomonas aeruginosa.

4a 18.22 4b 129.87 4c 7.83 4d 75.08 4e 66.67 4f 31.81 4g 7.95 4h 34.06 4i 58.00 4j 32.30 4k 64.59 4l Rifampicin 0.29 4m Isoniazid 5.25 4n Ethambutol 27.50 4o Ciprofloxacin 14.21

MIC (µM) P.aeruginosa

AC C

EP

TE D

M AN U

Penicillin Streptomycin

54.66 97.40 375.93 112.61 400 47.70 13.27 47.70 408.71 348.02 387.59 37.38 2.68

RI PT

MIC (µM) MTB H37Rv

SC

Entry

37

ACCEPTED MANUSCRIPT

Table 4. Anti TB evaluation of 5a-5r against M. smegmatis, M. tuberculosis H37RV, and Antibacterial activity against Pseudomonas aeruginosa. Entry

GI50 in µM

MIC (µM) MTB H37Rv

M. smegmatis

MIC (µM) P. aeruginosa

44.64 23.3 52.41 24.77 26.78 28.95

13.16 27.59 7.23 29.83 6.44 6.44

315.78 331.12 347.22 357.99 77.31 309.27

5g 5h

20.45 26.71

13.47 7.28

5i 5j

14 15.25

29.48 14.08

5k 5l 5m 5n 5o 5p 5q 5r Rifampicin Isoniazid

48.34 30.58 45.86 NA 73.91 NA 61.35 66.85 1.22 41.63

11.08 46.13 6.15 2.97 24.80 51.87 2.97 3.10 0.29 Penicillin 5.25 Streptomycin 27.50 14.21

RI PT

5a 5b 5c 5d 5e 5f

323.27 174.82

SC

M AN U

AC C

EP

TE D

Rifampicin Isoniazid Ethambutol Ciprofloxacin

38

353.77 337.83

265.95 276.75 295.27 285.71 297.61 311.20 285.71 297.61 37.38 2.68

ACCEPTED MANUSCRIPT

2

4c

3

4f

4

4g

5

4h

6

4i

7

4k

8

5a

9

5b

10

5c

11

5d

12

5e

13

5f

14

5g

15

5h

16

5i

17

5j

18 19

M AN U

4a

EP

1

% Cell inhibition IC50approximation (µM/mL) (IC50/MIC) 114.16 ˂˂50 82.41 ˂50 79.49 ˂50 32.01 ˃50 96.95 ˂50 78.24 ˂50 37.4 >50 89.85 ˂50 81.01 ˂50 72.36 ˂50 69.35 ˂50 62.55 ˂50 55.01 ˂50 49.26 >50 62.89 ˂50 65.14 ˂50 90.22 ˂50 86.74 ˂50 75.03 ˂50 38.32 >50 83.57 ˂50 68.83 ˂50 59.68 ˂50

SC

Compounds

TE D

S No

RI PT

Table 5. Percentage (%) of cell inhibition and selectivity index (SI) values of tetrasubstituted pyrrolyl-N-acetic acid and acetamides (4a-4k & 5a-5r) against HEK-293Tcell line.

5k

5m

5n

21

5o

22

5q

23

5r

AC C

20

39

SI index ~2.74

~6.38

~1.57

>6.29 ~1.47 ~.86 ~1.55 ~3.80 ~1.81 ~6.91 ~1.68 ~7.76 ~.76 ~3.71 ~6.86 ~1.70 ~3.55 ~4.51 ~8.13 ˃16.83 ~2.02 ~16.83 ~16.15

ACCEPTED MANUSCRIPT R1

+

O 1a

R2

R2

R2

(i)

(ii) R1

R3

R3

R1

O O

O

OH

3a

2a

R3

N

O 4a

(iii)

R1

N

RI PT

R2 R3 NHR4

SC

O 5a

M AN U

Scheme 1. Synthesis of title compounds 3,4 and 5.

Reagents and conditions: (i) 20 mol% bis-thiazolium salts, Et3N (1 equiv), EtOH, reflux 15 h; (ii) Amino acids (2 equiv), AcOH, reflux, 12 h; (iii) Compound 4 (1 mmol), HOBt (1.1 mmol), EDC.HCl (1.1 mmol), R4 (amine 1.2

AC C

EP

TE D

mmol), N,N-diisopropylethylamine (DIPEA) (1.2 mmol).

40

ACCEPTED MANUSCRIPT

Design, synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives P. Lakshmi Reddy,a M. Lakshmi Devi,c S. Satyanarayana,a Ashita Singh,b T.

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Veera Reddy,c J. Padma Sridevi,d G. Raja Sekhar,f P. Yogeeswari,d D. Sriram,d U.S.N.Murty,f Ramesh Ummanni, *b B. V. Subba Reddy,*e R. Narender,*a a

SC

Crop Protection Chemicals, Indian Institute of Chemical Technology, Tarnaka,

b

M AN U

Hyderabad -500 007, India.

Chemical Biology, Indian Institute of Chemical Technology, Tarnaka,

Hyderabad -500 007, India. c

d

Department of Pharmacy, Birla Institute of Technology & Science-Pilani,

Hyderabad Campus. e

TE D

Department of Chemistry, Vikrama Simhapuri University, Nellore- 524001.

EP

Natural Product Chemistry, Indian Institute of Chemical Technology, Tarnaka,

f

AC C

Hyderabad -500 007, India.

Biology Division Indian Institute of Chemical Technology, Tarnaka,

Hyderabad -500 007, India.

ACCEPTED MANUSCRIPT

Table of contents General procedure for the preparation of 1,2,3,5-tetrasubstituted pyrrolyl-Nacetic acid derivatives.

S1

2

General procedure for the preparation of 1,2,3,5-tetrasubstituted pyrrolyl-Nacetamide derivatives.

S2

3

experimental protocol of biological assay of anti-mycobacterial activity

S3

4

Plausible reaction mechanism of Paal-Knorr synthesis & amide coupling reaction.

S4

5

spectral data for compounds 4a-4k & 5a-5r.

S5

6

1

SC

RI PT

1

S6

M AN U

H and 13C NMR Spectrum for compounds 4a-4k & 5a-5r.

S1. General procedure for the preparation of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives.

TE D

Following the Paal-Knorr conditions, to a solution of diketone (1 g) in acetic acid (10 mL) was added amino acid (2 eq). The resulting mixture was heated in

EP

an oil bath at 120 oC. After completion, the mixture was cooled to room

AC C

temperature and concentrated in vacuo. The residue was dissolved in equal amount of ethyl acetate and water. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography.

S2. General procedure for the preparation of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives.

ACCEPTED MANUSCRIPT

Compound 4 (1 mmol) was dissolved in freshly dry dichloromethane under nitrogen atmosphere. Then HOBt (1.1 mmol), EDC.HCl (1.1 mmol) were added to the above solution. The resulting mixture was stirred for 5 min, and then (R4)

(1.2

mmol)

was

added

slowly

followed

by

N,N-

RI PT

amine

diisopropylethylamine (DIPEA) (1.2 mmol). The mixture was allowed to stir for 3h at room temperature. The progress of the reaction was monitored by TLC.

SC

After completion, the reaction mixture was quenched with water (10-15 mL)

M AN U

and extracted with dichloromethane. The organic layer was collected and dried over anhydrous Na2SO4 . The solvent was removed under reduced pressure and the resultant crude material was purified by column chromatography. S3. experimental protocol of biological assay of anti-mycobacterial activity.

TE D

S3.1 Screening against Mycobacterium.smegmatis. Anti-mycobacterial activity of newly prepared pyrrole derivatives was tested

EP

against Mycobacterium.smegmatis strain a good surrogate model using growth

AC C

inhibition assay by turbidometry (ref). Briefly, isolated single colonies of M. smegmatis MC2 155 from 7H10 agar plate were grown overnight in Middlebrook 7H9 medium (0.47% Middlebrook 7H9 broth base, 10% ADS, 0.2% glycerol, and 0.1% Tween-80) to mid exponential phase at 37 ºC. Subsequently, 5 mL of Middlebrook 7H9 broth were inoculated with overnight grown culture and allowed to grow at 37 ºC to early log phase (OD600 ≈ 0.3). For anti-microbial assay, 98 µL of 1:1000-folds dilution of secondary culture

ACCEPTED MANUSCRIPT

was dispensed into 96-well microtiter plate. To each well 2 µL of test compound was added to attain a final concentration of 6.25, 12.5, 25 and 50 µM, and allowed to grow at 37 ºC for 32 h. 240 µL of sterile water were added

RI PT

to each well of the peripheral rows of 96-well plate to minimize media evaporation during assay incubation. Bacterial growth was assessed after 32 h of incubation by measuring turbidity at 600 nm (OD600) values using

SC

TECANInfinite 200 PRO™ (Tecan Instruments, Switzerland). Positive controls

M AN U

were included in every assay plates using stock solutions of INH (10 mg/mL, HiMedia) and Rifampicin (10 mg/mL, HiMedia) to achieve the final concentration of 0.5, 1, 2, 4, 8 and 16 µg/mL for INH and 0.25, 0.5, 1,2,4 and 8 µg/mL for Rifampicin. Additional controls DMSO (solvent without compound)

TE D

and medium without inoculum were included in all the assay plates avoiding intra assay variability. The results were analyzed with respect to the percentage

EP

of growth inhibition. All experiments were carried out in triplicates and the results were reported as ± SD.

AC C

S3.2 Screening against Mycobacterium.tuberculosis. Two-fold serial dilutions of each test compound/drug were prepared and incorporated into Middle- brook 7H11 agar medium with oleic acid, albumin, dextrose, and catalase (OADC) growth supplement to get final concentrations of 50, 25, 12.5, 6.25, 3.13, 1.56, and 0.78 µg/mL. Inoculum of M. tuberculosis (H37Rv ATCC 27294) was prepared from fresh Middlebrook 7H11 agar slants

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with OADC (Difco) growth supplement adjusted to 1 mg/ mL (wet weight) in Tween 80 (0.05%) saline diluted to 10−2 to give a concentration of ∼107 cfu/mL. Five microliters of this bacterial suspension was spotted onto 7H11 agar tubes

RI PT

containing different concentrations of the drug as discussed above. The tubes were incubated at 37 °C, and final readings (as MIC in µg/mL) were determined after 28 days. The MIC is defined as the minimum concentration of compound

SC

required giving complete inhibition of bacterial growth. All experiments were

S3.3 Cytotoxicity assay.

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carried out in triplicates and the results were reported in table.

Most active compounds were further examined for toxicity in a HEK293T cell line at the concentration of 50 µM. After 72 h of exposure, viability was

TE D

assessed on the basis of cellular conversion of MTT into a formazan product

AC C

EP

using the Promega Cell Titer 96 non-radioactive cell proliferation assay

ACCEPTED MANUSCRIPT

S4. Plausible reaction mechanism of Paal-Knorr synthesis & amide coupling reaction.

TE D

M AN U

SC

RI PT

Mechanism of the Paal-Knorr synthesis.

AC C

EP

Mechanism of the amide coupling reaction

ACCEPTED MANUSCRIPT HCl

N

H N

N

N N

O

+

N

O

O

N

C

R

N . HCl

N

N . HCl

O N H

N H

N N

O

N

R

S O +

R=

.. H2N

N N N

S N

M AN U

N OH

N

O

SC

R

H N

N OH ..

RI PT

OH

+

S5. spectral data for compounds 4a-4k & 5a-5r.

(4a).

TE D

4.1.1 (Table 1): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic acid

White solid, mp: 143-145 °C; Yield: 95%; 1H NMR (300 MHz, CDCl3): δ 7.48-

EP

7.33 (m, 5H, Ar-H), 7.28 (t, J = 6.7 Hz, 3H, Ar-H), 7.22 (d, J = 8.8 Hz, 2H, Ar-

AC C

H ), 7.15 (t, J = 6.7 Hz, 1H, Furan-H), 6.40 (s, 1H, Pyrrole- H), 6.38 (d, J = 3.2 Hz, 1H, Furan-H), 6.25 (d, J = 3.2 Hz, 1H, Furan-H) 4.63 (s, 2H, CH2);

13

C

NMR (75 MHz, CDCl3): δ 47.2, 109.8, 111.1, 111.4, 121.3, 126.1, 126.4, 127.8, 127.9, 128.1, 128.7, 129.0, 132.2, 135.4, 136.8, 142.6, 145.6, 175.4; IR (KBr): υ 760, 1069, 1239, 1483, 1728, 2939, 3069 cm-1; ESI-MS: m/z: 366 [M+Na]+; HRMS (ESI) calcd for C22H17NO3Na, 366.1106 [M+Na]+, found: 366.1103.

ACCEPTED MANUSCRIPT

4.1.2

(Table

1):

2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1yl)-3-

methylbutan oic acid (4b). White solid, mp: 121-123 °C; Yield: 69%; 1H NMR (300 MHz, CDCl3): δ 7.56

RI PT

(t, J=6.7 Hz, 1H, Ar-H) 7.49-7.37(m, 4H, Ar-H), 7.30-7.19 (m, 5H, Ar-H), 7.17 (d, J = 3.0 Hz, 1H, Furan-H), 6.46 (s, 1H Pyrrole-H), 6.42 (t, J = 3.1 Hz, 1H,

SC

Furan-H), 6.38 (d, J = 3.1 Hz, 1H, Furan-H), 4.45 (d, J = 10.5 Hz, 1H, CH), 2.05-1.92 (m, 1H, CH), 0.88 (d, J = 6.2 Hz, 3H, CH3 ), 0.50 (d, J = 6.6 Hz, 3H, 13

C NMR (75MHz, CDCl3): δ 18.6, 21.8, 64.5, 109.0, 111.3, 113.2,

M AN U

CH3);

119.4, 125.9, 127.3, 127.6, 127.9, 128.1, 128.5, 129.8, 132.9, 135.4, 138.3, 142.6, 145.1, 176.4; IR (KBr): υ 761, 852, 1232, 1510, 1708, 2843, 3026 cm-1;

TE D

ESI-MS: m/z: 386 [M+H]+.

4.1.3 (Table 1): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1yl)-3-methyl pent

EP

anoic acid (4c).

Brown solid, m.p: 112-114 °C; Yield: 61%; 1H NMR (300 MHz, CDCl3): δ 7.50

AC C

(t, J = 7.5 Hz, 3H, Ar-H), 7.42 -7.34 (m, 2H, Ar-H), 7.29 -7.17 (m, 5H, Ar-H), 7.13 (d, J=6.7 Hz, 1H, Furan-H), 6.42 (t, J = 3.0 Hz, 1H, Furan-H), 6.39 (s, 1H, Pyrrole- H), 6.29 (d, J = 3.0 Hz, 1H, Furan-H), 4.91 (dd, J = 4.5, 11.3 Hz, 1H, CH), 1.61-1.45 (m, 2H, CH2), 0.92-0.81 (m, 1H, CH), 0.61 (d, J = 6.7 Hz, 3H), 0.48 (d, J = 6.0 Hz, 3H); 13C NMR (75MHz, CDCl3): δ 20.9, 22.8, 24.0, 38.9, 57.2, 109.4, 111.5, 112.1, 125.9, 127.5, 127.9, 128.1, 128.6, 128.6, 129.4,

ACCEPTED MANUSCRIPT

132.9, 137.8, 142.2, 174.7; IR (KBr): υ 759, 1033, 1248, 1511, 1710, 2955, 3420 cm-1; ESI-MS: m/z: 400 [M+H]+, 422 [M+Na]+. 4.1.4 (Table 1): 2-(2-3di(furan-2-yl)-5-phenyl-1H-pyrrol-1-yl)acetic acid

RI PT

(4d).

Brown solid, m.p: 125-127 °C; Yield: 79%; 1H NMR (300 MHz, CDCl3): δ 7.49

SC

(d, J = 1.5 Hz, 1H, Furan-H), 7.42-7.32 (m, 5H, Ar-H), 7.31 (d, J = 1.5 Hz, 1H, Furan-H), 6.55 (d, J = 3.7 Hz, 1H, Furan-H), 6.52 (s, 1H, Pyrrole-H), 6.48 (t, J

M AN U

= 5.2 Hz, 1H, Furan-H), 6.29 (t, J = 5.2 Hz, 1H, Furan-H), 6.08 (d, J = 3.7 Hz, 1H, Furan-H), 4.56 (s, 2H, CH2);

13

C NMR (75 MHz, CDCl3): δ 47.0, 104.5,

107.8, 109.0, 109.1, 110.9, 111.1, 111.9, 123.2, 127.3, 127.9, 128.4, 128.6,

TE D

128.8, 128.9, 129.0, 136.8, 140.4, 142.8, 174.2; IR (KBr): υ 670, 836, 1017, 1238, 1486, 1724, 2972, 3059 cm-1; ESI-MS: m/z: 334 [M+H]+; HRMS (ESI)

4.1.5

EP

calcd for C20H16O4N 334.1079 [M+H]+, found: 334.1086. (Table

1):

2-(2-3-di(furan-2-yl)5-phenyl-1H-pyrrol-1yl)-3-

AC C

methylbutano ic acid (4e).

Brown solid, m.p: 110-112 °C; Yield: 75%; 1H NMR (300 MHz, CDCl3): δ 7.54 (d, J = 6.3 Hz, 2H, Furon-H) 6.49-6.33 (m, 5H, Ar-H), 6.58 (d, J = 4.7 Hz, 1H, Furan-H), 6.57 (s, 1H, Pyrrole-H), 6.49 (t, J = 3.1 Hz, 1H, Furan-H), 6.31 (t, J = 3.1 Hz, 1H, Furan-H), 5.88 (d, J = 3.1 Hz, 1H, Furan-H), 4.41 (s, 1H, CH), 1.98-1.87 (m, 1H, CH), 0.85 (d, J = 6.2 Hz, 3H, CH3), 0.50 (d, J = 6.6 Hz,

ACCEPTED MANUSCRIPT

3H,CH3);

13

C NMR (75MHz, CDCl3): δ 18.7, 21.7, 64.5, 104.0, 107.0, 111.0,

111.2, 113.4, 118.4, 118.6, 128.1, 128.6, 129.9, 132.6, 138.4, 140.3, 142.9, 144.4, 149.9, 176.2; IR (KBr): υ 753, 865, 1246, 1615, 1721, 2867, 3015 cm-1;

RI PT

ESI-MS: m/z: 376 [M+H]+, 398 [M+Na]+. 4.1.6 (Table 1): 2-(2-(furan-2-yl)-5-(naphthalene-1-yl)-3-phenyl-1H-pyrrol-

SC

1-yl)acetic acid (4f).

M AN U

White solid, m.p: 138-140 °C; Yield: 85%; 1H NMR (300 MHz, CDCl3): δ 7.97 (d, J = 8.3 Hz, 1H, Ar-H ), 7.81 (d, J = 9.0 Hz, 1H, Ar-H), 7.76 (t, J = 4.5 Hz, 1H, Ar-H), 7.50 (d, J = 6.7 Hz, 2H, Ar-H), 7.46-7.30 (m, 7H, Ar-H), 7.25 (d, J = 1.5 Hz, 1H, Furan-H), 6.39 (s, 1H, Pyrrole-H), 6.10 (dd, J = 1.5, J = 3.0 Hz,

TE D

1H, Furan-H) 5.63 (d, J = 3.7 Hz, 1H, Furan-H), 4.87 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 47.3, 110.3, 111.2, 111.4, 121.7, 126.1, 126.3, 126.5, 126.6, 126.8, 127.7, 127.8, 127.9, 128.0, 128.2, 128.4, 129.6, 132.6, 133.3,

EP

135.5, 136.8, 142.7, 145.6, 174.6; IR (KBr): υ 709, 802, 1221, 1602, 1726,

AC C

3054 cm-1; ESI-MS: m/z: 416 [M+Na]+; HRMS (ESI) calcd for C26H19O3NNa 416.1262 [M+Na]+, found: 416.1244. 4.1.7 (Table 1): 2-(2-(furan-2-yl)-3-(naphthalene-1-yl)-5-phenyl-1H-pyrrol1-yl)acetic acid (4g). White solid, m.p: 145-147 °C; Yield: 84%; 1H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H, Ar-H), 7.86 (d, J = 8.9 Hz, 1H, Ar-H), 7.85-7.81 (m, 2H, Ar-H), 7.55 (d,

ACCEPTED MANUSCRIPT

J = 8.9 Hz, 1H, Furan-H), 7.50-7.47 (m, 3H, Ar-H), 7.31 (d, J = 7.9 Hz, 2H), 7.24 (t, J = 7.9 Hz, 3H, Ar-H), 7.15 (t, J = 6.9 Hz, 1H, Ar-H), 6.50 (s, 1H, Pyrrole-H), 6.37 (t, J = 2.9 Hz, 1H, Furan-H ), 6.27 (d, J = 2.9 Hz, 1H, Furan-

RI PT

H), 4.70 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 47.9, 109.1, 111.0, 112.4, 123.6, 123.7, 125.3, 125.5, 125.7, 126.4, 127.1, 127.7, 127.8, 127.9, 128.7, 128.9, 129.0, 133.6, 141.3, 146.1, 175.3; IR (KBr): υ 761, 864, 1247, 1449,

M AN U

394.1443 [M+H]+, found: 394.1440.

SC

1503, 1602, 1725, 2926, 3056 cm-1; HRMS (ESI) calcd for C26H20O3N

4.1.8 (Table 1): 2-(2,3,5-triphenyl-1H-pyrrol-1-yl)acetic acid (4h). White solid, mp: 135-137 °C; Yield: 74%;1H NMR (300 MHz, CDCl3): δ 7.39

TE D

(d, J = 7.7 Hz, 2H, Ar-H), 7.37 (t, J = 9.8 Hz, 1H, Ar-H), 7.34-7.26 (m, 7H, ArH), 7.06 (t, J = 8.0 Hz, 4H, Ar-H), 6.99 (t, J = 6.9 Hz, 1H, Ar-H), 6.47 (s, 1H, Pyrrole-H), 4.50 (s, 2H, CH2); 13C NMR (75MHz, CDCl3): δ 46.6, 109.5, 123.3,

EP

125.3, 127.6, 128.0, 128.2, 128.6, 128.8, 129.0, 131.2, 132.2, 132.5, 132.7,

AC C

135.6, 135.7, 174.8; IR(KBr): υ 703, 777, 1008, 1223, 1346, 1478, 1722, 3054 cm-1; HRMS (ESI) calcd for C24H20O2N 354.1494 [M+H]+, found: 354.1503. 4.1.9 (Table 1): 2-(3,5diphenyl-2-p-tolyl-1H-pyrrol-1-yl)acetic acid (4i). White solid, mp: 124-126 °C Yield: 86%; 1H NMR (300 MHz, CDCl3): δ 7.377.30, (m, 4H, Ar-H), 7.24 (t, J = 8.8 Hz, 6H, Ar-H), 7.19 (d, J = 6.9 Hz, 4H, ArH) 6.50 (s, 1H, Pyrrole-H), 4.51 (s, 2H), 2.41 (s, 3H, CH3); 13C NMR (75MHz,

ACCEPTED MANUSCRIPT

CDCl3): δ 21.2, 46.9, 109.3, 109.5, 123.8, 127.4, 128.6, 129.0, 129.3, 129.4, 129.5, 130.0, 130.9, 130.9, 133.0, 136.6, 136.9, 137.4, 139.9, 175.1; IR (KBr): υ 755, 824, 1223, 1601, 1706, 2822, 3028 cm-1; ESI-MS: m/z: 390 [M+Na]+.

RI PT

4.1.10 (Table 1): 2-(2-(4-bromophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic acid (4j).

SC

White solid, mp: 194-196 °C; Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 7.49 (d, J = 8.3 Hz, 2H, Ar-H) 7.45-7.40 (m, 4H, Ar-H), 7.39-7.35 (m, 1H, Ar-H)

4.49 (s, 2H, CH2);

13

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7.20 (t, J = 4.1 Hz, 6H, Ar-H), 7.13-7.09 (m, 1H, Ar-H) 6.45 (s, 1H, Pyrrole-H), C NMR (75MHz, CDCl3): δ 46.7, 108.8, 121.5, 122.4,

125.3, 127.1, 127.3, 128.1, 128.3, 128.6, 130.4, 131.5, 131.6, 132.3, 132.8,

TE D

135.2, 135.4, 170.4; IR (KBr): υ 743, 842, 1234, 1591, 1721, 2923, 3034 cm-1; HRMS (ESI) calcd for C24H18O2NNa 454.0414 [M+Na]+, found: 454.0416.

acid (4k).

EP

4.1.11 (Table 1): 2-(2-(4-chlorophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic

AC C

White solid, mp:143-145 °C; Yield: 90%; 1H NMR: (300 MHz, CDCl3): δ 7.77-7.69 (m, 1H, Ar-H), 7.49 (d, J = 4.5 Hz, 1H, Ar-H), 7.44 (t, J = 8.3 Hz, 1H, Ar-H), 7.39-7.31 (m, 5H, Ar-H), 7.19 (d, J = 6.2 Hz, 5H, Ar-H), 7.10 (t, J = 6.2 Hz, 1H, Ar-H), 6.49 (s, 1H, Pyrrole-H), 4.43 (s, 2H, CH2);

13

C NMR (75

MHz, CDCl3 +DMSO-d6): δ 46.7, 109.1, 122.8, 124.9, 125.7, 126.0, 126.3, 126.7, 127.0, 127.1, 127.4, 127.7, 128.4, 129.6, 130.6, 130.7, 131.8, 132.1,

ACCEPTED MANUSCRIPT

132.7, 133.2, 135.2, 135.2, 170.6; IR (KBr): υ 699, 768, 1043, 1204, 1452, 1708, 3018 cm-1; ESI-MS: m/z: 387 [M+] 389 [M+2H]+. 4.2.1 (Table 2): N-(benzo[d]thiazol-2yl)-2-(furan-2-yl)-3,5-diphenyl-1H-

RI PT

pyrrol -1-yl)acetamide (5a).

White solid, m.p: 113-115 ºC; Yield: 78%; 1H NMR (300 MHz, CDCl3): δ 7.78

SC

(d, J = 7.5 Hz, 1H, Ar-H) 7.53 (d, J = 8.3 Hz, 1H, Ar-H), 7.45-7.17 (m, 13H, Ar-H, Furan-H), 6.52 (s, 1H, Pyrrole-H), 6.34 (t, J = 3.0 Hz, 1H, Furan-H ),

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6.28 (d, J = 3.0 Hz, 1H, Furan-H), 4.75 (s, 2H, CH2);

13

C NMR (75 MHz,

CDCl3): δ 49.4, 110.9, 111.3, 112.0, 120.8, 121.4, 124.2, 126.4, 127.6, 127.9, 128.3, 128.9, 131.5, 132.0, 135.0, 137.1, 143.1, 144.9, 147.8, 157.4, 167.5; IR

TE D

(KBr): υ 758, 1271, 1545, 1703, 2924, 3060, 3351 cm-1; ESI-MS: m/z: 476 [M+H]+, 498 [M+Na]+; HRMS (ESI) calcd for C29H21N3O2NaS, 498.1252

4.2.2

(Table

EP

[M+Na]+, found: 498.1258. 2):

N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(furan-2-yl)-3,5-

AC C

dipheny l-1H-pyrrol-1-yl)acetamide (5b). White solid, m.p: 236-238 °C; Yield: 81%; 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 7.5 Hz, 1H, Ar-H),7.80 (d, J = 7.7 Hz, 1H, Ar-H), 7.75 (d, J = 3.0 Hz, 1H, Ar-H), 7.56 (d, J = 6.7 Hz, 2H, Ar-H), 7.45-7.27 (m, 5H, Ar-H), 7.01 (d, J = 3.3 Hz, 1H, Furan-H), 6.44 (s, 1H, Pyrrole-H), 5.99 (t, J = 3.0 Hz, 1H, FuranH), 5.65 (d, J = 3.0 Hz, 1H, Furan-H), 5.21. (s, 2H, CH2), 3.02 (qt, 2H, CH2),

ACCEPTED MANUSCRIPT

1.40 (t, J = 7.5 Hz, 3H, CH3);13C NMR (75 MHz, CDCl3): δ 13.6, 22.5, 47.8, 108.6, 111.2, 111.7, 121.0, 125.3, 125.7, 126.7, 127.6, 128.1, 128.4, 128.6, 131.8, 135.0, 136.4, 143.6, 144.6, 157.5. 165.6. 166.9; IR (KBr): υ 761, 1307,

RI PT

1570, 1707, 2872, 3055 cm-1; ESI-MS: m/z: 477 [M+Na]+; HRMS (ESI) calcd for C26H22N4O2NaS, 477.1361 [M+Na]+, found: 477.1369. (Table

2):

N-benzyl-2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-

SC

4.2.3

yl)aceta mide (5c).

M AN U

White solid, m.p: 178-180 °C; Yield: 80%; 1H NMR (300 MHz, CDCl3): δ 7.43-7.34 (m, 6H, Ar-H),7.32-7.25 (m, 7H, Ar-H), 7.22-7.16 (m, 3H, Ar-H), 6.51 (s, 1H, Pyrrole-H), 6.39 (dd, J = 1.8, 3.3 Hz, 1H, Furan-H), 6.25 (d, J = 3.0

TE D

Hz, 1H, Furan-H), 5.99-5.92. (m, 1H, Ar-H), 4.63 (s, 2H, CH2), 4.44 (d, J = 7.5 Hz, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 43.2, 49.3, 110.3, 111.1, 111.9, 120.2, 121.3, 125.1, 126.2, 127.2, 127.4, 127.5, 127.6, 128.0, 128.2, 128.5,

EP

128.7, 131.6, 135.0, 136.9, 137.6, 142.9, 144.9, 168.7; IR (KBr): υ 759, 1248,

AC C

1557, 1661, 2924, 3064 cm-1; ESI-MS: m/z: 433 [M+H]+; HRMS (ESI) calcd for C29H25N2O2, 433.1916 [M+ H]+, found: 433.1931. 4.2.4 (Table 2): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-yl)-N-(pyridin2-yl)acetamide (5d). White solid, m.p: 118-120 °C; Yield:74%; 1H NMR (300 MHz, CDCl3): δ 8.18 (d, J = 6.7 Hz, 2H, Pyridine-H), 7.66 (t, J = 7.5 Hz, 1H, Ar-H), 7.45 (d, J = 7.5

ACCEPTED MANUSCRIPT

Hz, 3H, Ar-H), 7.38 (t, J = 7.5 Hz, 2H, Pyridine-H), 7.35-7.29 (m, 3H, Ar-H, Furan-H), 7.25 (t, J = 6.7 Hz, 2H, Ar-H), 7.16 (t, J = 7.5 Hz, 1H, Ar-H), 7.00 (t, J = 6.0 Hz, 1H, Ar-H), 6.54 (s, 1H, Pyrrole-H), 6.35 (t, J = 3.7 Hz, 1H, Furan-

RI PT

H), 6.29 (d, J = 3.7 Hz, 1H, Furan-H). 4.65 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 49.9, 110.6, 111.2, 112.0, 114.0, 120.2, 126.2, 127.7, 128.0, 128.2, 128.8, 128.9, 131.7, 135,1, 137.0, 138.3, 143.0, 145.0, 147.8, 150.5, 167.4; IR

420.1707.

C27H22N3O2, 420.1712 [M+H]+, found:

M AN U

[M+H]+, HRMS (ESI) calcd for

SC

(KBr): υ 778 , 1306, 1447, 1571, 1712, 2926, 3054 cm-1; ESI-MS: m/z: 420

4.2.5 (Table 2): N-(2-(1H-indol-3-yl)ethyl)-2-(2-(furan-2-yl)-3,5-diphenyl-

TE D

1H-pyrrol-1-yl)acetamide (5e).

Orange solid, m.p: 105-107 °C; Yield: 88%; 1H NMR (300 MHz, CDCl3): δ 7.77 (s, 1H, Indole-H), 7.48 (d, J = 7.5 Hz, 1H, Ar-H), 7.28 (t, J = 3.1 Hz, 6H,

EP

Ar-H), 7.21 (d, J = 7.3 Hz, 2H, Ar-H), 7.15 (t, J = 8.1 Hz, 3H, Ar-H), 7.03 (t, J

AC C

= 7.9 Hz, 1H, Ar-H), 6.71 (d, J = 1.5 Hz, 1H, Ar-H), 6.41, (s, 1H, Pyrrole-H), 6.29. (t, J = 1.7 Hz, 1H, Furan-H), 6.00 (d, J = 3.0 Hz, 1H, Furan-H), 5.60 (t, J = 4.3 Hz, 1H, Furan-H). 4.42 (s, 2H, CH2), 3.51 (qt, 2H, CH2), 2.86 (t, J = 6.4 Hz, 2H, CH2);

13

C NMR (75 MHz, CDCl3): δ 24.8, 38.8, 49.2, 109.8, 111.1,

111.2, 111.9, 112.0, 118.5, 119.3, 120.9, 122.2, 126.3, 126.8, 126.9, 127.3, 127.9, 128.4, 128.7, 128.7, 131.5, 135.1, 136.4, 136.7, 143.0, 144.6, 168.6; IR (KBr): υ 698, 1228, 1526, 1663, 2925, 3025, 3296 cm-1; ESI-MS: m/z: 486

ACCEPTED MANUSCRIPT

[M+H]+, 508 [M+Na]+; HRMS (ESI) calcd for C32H27N3O2Na, 508.2000 [M+Na]+, found: 508.1993. 4.2.6 (Table 2): N-(benzo[d]thiazol-2yl)-2-(2,3,5-triphenyl-1H-pyrrol-1-yl)

RI PT

ac etamide (5f).

White solid, m.p: 129-131 °C; Yield: 76%; 1H NMR (300 MHz, CDCl3): δ 7.76

SC

(d J = 7.9 Hz, 1H, Ar-H), 7.49 (t, J = 7.9 Hz, 3H, Ar-H), 7.40-7.25 (m, 11H, ArH), 7.18 (t, J = 7.1Hz, 2H, Ar-H), 7.14 (d, J = 7.5 Hz, 1H, Ar-H), 7.07 (t, J =

M AN U

6.7 Hz 1H, Ar-H), 6.57 (s, 1H, Pyrrole-H), 4.67 (s, 2H, CH2);

13

C NMR (75

MHz, CDCl3): δ 48.7, 110.5, 120.6, 121.4, 124.2, 124.3, 125.6, 126.4, 127.7, 128.0, 128.1, 128.4, 128.9, 129.1, 131.9, 132.1, 132.2, 135.3, 135.7, 147.7,

TE D

157.8, 157.9, 167.5; IR (KBr): υ 756, 1271, 1555, 1601, 1709, 2925, 3057 cm-1; ESI-MS: m/z: 486 [M+H]+, 508 [M+Na]+; HRMS (ESI) calcd for C31H24N3OS,

4.2.7

(Table

EP

486.1640 [M+H]+, found: 486.1655. 2):

N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2,3,5-triphenyl-1H-

AC C

pyrrol-1-yl)acetamide (5g).

White solid, m.p: 182-184 °C; Yield: 82%; 1H NMR (300 MHz, CDCl3): δ 7.50 (d, J = 6.9 Hz, 2H, Ar-H), 7.39 (t, J = 7.3 Hz, 1H, Ar-H), 7.30 (t, J = 6.6 Hz, 3H, Ar-H ), 7.25 (d, J = 8.3 Hz, 1H, Ar-H), 7.21 (d, J = 7.5 Hz, 1H, Ar-H), 7.17-7.08 (m, 6H, Ar-H ), 7.02 (t, J = 6.9 Hz, 1H, Ar-H), 6.52 (s, 1H, PyrroleH), 4.86 (s, 2H, CH2), 2.99 (qt, 2H, CH2), 1.40 (t, J = 7.5 Hz, 3H, CH3);

13

C

ACCEPTED MANUSCRIPT

NMR (75 MHz, CDCl3): δ 13.7, 22.6, 47.7, 108.8, 122.1, 125.2, 127.0, 127.4, 128.1, 128.3, 128.4, 128.7, 130.9, 132.0, 132.2, 132.4, 135.2, 135.6, 157.6, 165,8, 167.4; IR (KBr): υ 754, 1303, 1560, 1717, 2922, 3050 cm-1; ESI-MS:

RI PT

m/z: 465 [M+H]+; HRMS (ESI) calcd for C28H25ON4S, 465.17592 [M+H]+, found: 465.17436. (Table

2):

N-(pyridin-2-yl)-2-(2,3,5-triphenyl-1H-pyrrol-1-

SC

4.2.8

yl)acetamide (5h).

M AN U

White solid, mp: 103-105 °C Yield: 75%; 1H NMR (300 MHz, CDCl3): δ 8.12 (t J=8.6Hz,1H, Ar-H), 7.68 (t, J = 7.3 Hz, 1H, Ar-H), 7.48 (d, J = 6.6 Hz, 1H, Ar-H), 7.41 (t, J = 6.6 Hz, 1H, Ar-H), 7.37-7.26 (m, 9H, Ar-H), 7.15 (t, J = 8.6

TE D

Hz, 4H, Ar-H), 7.06 (d, J = 6.7 Hz, 1H, Ar-H), 7.01 (t, J = 7.3 Hz, 1H, Ar-H), 6.57 (s, 1H, Pyrrole-H), 4.59 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 48.7, 110.5, 120.6, 121.4, 124.2, 124.3, 125.6, 126.4, 127.7, 128.0, 128.1, 128.4,

EP

128.8, 128.9, 129.1, 131.0, 131.9, 132.1, 132.2, 135.3, 135.7, 147.7, 157.8,

AC C

167.5; IR (KBr): υ 755, 1191, 1303, 1561, 1716, 2934, 3050 cm-1. ESI-MS: m/z: 430 [M+H]+, 452[M+Na]+; HRMS (ESI) calcd for C29H24N3O, 430.1919 [M+H]+, found: 430.1900. 4.2.9 (Table 2): N-(benzo[d]thiazol-2-yl)-2-(2,3-di(furan-2-yl)-5-phenyl-1Hpyrrol-1-yl)acetamide (5i).

ACCEPTED MANUSCRIPT

Brown solid, m.p: 112-114 °C; Yield: 79%, 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H, Furan-H), 7.70 (d, J = 7.5 Hz, 1H, Furan-H), 7.50-7.28 (m, 9H, Ar-H), 6.68 (s, 1H, Pyrrole-H), 6.62 (d, J = 3.7 Hz, 1H, Furan-H), 6.47 (t, J

1H, Furan-H), 4.76 (s 2H, CH2);

13

RI PT

= 3.0 Hz, 1H, Furan-H), 6.38 (t, J = 3.0 Hz, 1H, Furan-H), 6.20 (d, J = 3.0 Hz, C NMR (75 MHz, CDCl3): δ 49.3, 105.1,

109.0, 111.0, 111.3, 112.2, 118.2, 120.4, 120.9, 121.4, 124.2, 126.4, 126.6,

SC

128.4, 128.9, 129.0, 131.2, 137.1, 140.8, 143.3, 144.2, 147.9, 149.3, 157.2,

M AN U

167.2; IR (KBr): υ 761, 1306, 1567, 1709, 2934, 3050 cm-1; ESI-MS: m/z: 465 [M+H]+.

4.2.10 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2,3-di(furan-2-yl)-5-

TE D

phenyl -1H-pyrrol-1-yl)acetamide (5j).

Brown solid, mp: 117-119 °C Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 7.47 (d, J = 6.7 Hz, 1H, Furan-H), 7.37-7.26 (m, 5H, Ar-H), 6.77 (t, J = 3.5 Hz, 1H,

EP

Furan-H) 6.58 (s, 1H, Pyrrole-H) 6.51 (d, J = 3.1 Hz, 1H, Furon-H), 6.28 (t, J =

AC C

2.2 Hz, 2H, Furan-H), 6.05 (d, J= 3.0 Hz, 1H Furan-H), 4.92 (s, 2H, CH2), 3.00 (qt, 2H, CH2), 1.39 (t, J = 7.5 Hz, 3H, CH3);

13

C NMR (75 MHz, CDCl3): δ

13.6, 22.5, 48.5, 109.4, 110.9, 111.5, 122.8, 123.3, 125.3, 125.5, 125.7, 126.9, 127.4, 127.6, 127.9, 128.4, 128.7, 131.7, 131.8, 133.2, 133.6, 136.1, 142.5, 145.2, 165.6, 167.2; IR (KBr): υ 702, 1214, 1338, 1603, 1718, 2926 cm-1; ESIMS: m/z: 445 [M+H]+; HRMS (ESI) calcd for C24H21N4O3 S, 445.1328 [M+H]+, found: 445.1329.

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4.2.11

(Table

2):

N-(benzo[d]thiazol-2-yl)-2-(2-(4-bromophenyl)-3,5-

diphenyl-1H-pyrrol-1-yl) acetamide (5k). White solid, m.p: 111-113 °C; Yield:80%, 1H NMR (300 MHz, CDCl3): δ 7.79

RI PT

(d, J = 5.2 Hz, 1H, Ar-H), 7.52 (d, J = 8.3 Hz, 1H, Ar-H) 7.45 (t, J = 8.3 Hz, 4H, Ar-H), 7.36 (t, J = 6.7 Hz, 2H, Ar-H), 7.32-7.29 (m, 2H, Ar-H), 7.25-7.17

2H, CH2);

13

SC

(m, 7H, Ar-H), 7.12 (t, J = 4.5 Hz, 1H, Ar-H) 6.62 (s, 1H, Pyrrole-H), 4.65 (s, C NMR (75 MHz, CDCl3): δ 48.7, 110.9, 120.6, 121.5, 122.8,

M AN U

124.3, 125.9, 126.5, 127.8, 128.1, 128.2, 128.9, 129.0, 130.8, 131.9, 132.2, 132.6, 135.0, 136.2, 147.6, 157.7, 167.3; IR (KBr): υ 757, 1270, 1553, 1709, 2926, 3057 cm-1; ESI-MS: m/z: 564 [M]+, HRMS (ESI) calcd for

TE D

C31H23ON3BrS, [M]+, 564.07397 found:564.07579.

4.2.12 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(4-bromophenyl)-3,5-

EP

diphenyl-1H-pyrrol-1-yl) acetamide (5l). White solid, m.p: 226-228 °C; Yield: 74%; 1H NMR (300 MHz, CDCl3): δ 7.44

AC C

(d, J = 7.9 Hz, 4H, Ar-H), 7.37 (t, J = 6.9 Hz, 2H, Ar-H), 7.29 (t, J = 6.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.9 Hz, 2H, Ar-H), 7.16 (d, J = 4.9 Hz, 4H, Ar-H), 7.07 (t, J = 4.9 Hz, 1H, Ar-H), 6.44 (s, 1H, Pyrrole-H), 4.61 (s, 2H, CH2), 3.02 (qt, 2H, CH2), 1.41 (t, J = 7.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 13.6, 22.6, 47.7, 106.4, 109.0, 109.7, 119.7, 121.6, 122.6, 125.3, 127.1, 127.4, 128.2, 128.4, 128.6, 129.0, 130.6, 131.4, 131.7, 132.2, 132.9, 135.4, 135.6, 142.7, 157.4, 165.7, 167.2; IR (KBr): υ 758, 1131, 1574, 1709, 2924, 3051 cm-1; ESI-

ACCEPTED MANUSCRIPT

MS: m/z: 545 [M+2H]+; HRMS (ESI) calcd for C28H25BrN4OS, 545.0826 [M+2H]+, found: 545.07805. 4.2.13 (Table 2): 2-(2-(4-bromophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)-N-

RI PT

(pyri din-2-yl)acetamide (5m).

White solid, m.p: 175-177 °C; Yield: 69%; 1H NMR (300 MHz, CDCl3): δ 8.15

SC

(d, J = 4.1 Hz, 1H, Pyridine-H ), 8.05 (d, J = 8.1 Hz, 1H, Pyridine-H), 7.64 (t, J = 8.3 Hz, 1H, Pyridine-H), 7.46 (d, J = 7.9 Hz, 3H, Ar-H), 7.39 (t, J = 6.9 Hz,

M AN U

1H, Ar-H), 7.31 (t, J = 7.1 Hz, 1H, Ar-H), 7.25-7.15 (m, 8H, Ar-H), 7.11 (t, J = 7.9 Hz, 1H, Pyridine-H), 7.00 (t, J = 6.2 Hz, 1H, Ar-H), 6.59 (s, 1H, Pyrrole-H), 4.58 (s, 2H, CH2);

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C NMR (75 MHz, CDCl3): δ 48.2, 108.7, 113.4, 119.6,

TE D

121.5, 122.3, 125.2, 127.0, 127.3, 128.1, 128.3, 128.5, 130.6, 131.5, 132.3, 132.9, 135.5, 138.2, 147.9, 151.1, 167.5; IR (KBr): υ 756, 1300, 1482, 1689, 2941, 3294 cm-1; ESI-MS: m/z: 508 [M]+, 510 [M+2H]+; HRMS (ESI) calcd for

EP

C29H24BrN3O 510.1908, found: 510.1203.

AC C

4.2.14 (Table 2): N-(benzo[d]thiazol-2-yl)-2-(2-(furan-2-yl)-5-(naphthalen2-yl)-3-phenyl-1H-pyrrol-1-yl)acetamide (5n). White solid, m.p:122-124 °C; Yield: 79%; 1H NMR (300 MHz, CDCl3): δ 7.90 (d J = 8.3 Hz, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.85-7.79 (m, 3H, Ar-H), 7.72 (d, J = 7.5 Hz, 1H, Ar-H), 7.55 (dd, J = 6.7, 8.3 Hz, 1H, Furan-H), 7.51-7.47 (m, 2H, Ar-H), 7.45 (t, J = 3.0 Hz, 2H, Ar-H), 7.40 (d, J = 7.1 Hz, 2H, Ar-H), 7.37-

ACCEPTED MANUSCRIPT

7.30 (m, 3H, Ar-H), 7.24 (t, J = 6.7 Hz, 1H, Ar-H), 6.68 (s, 1H, Pyrrole-H), 6.37 (t, J = 3.0 Hz, 1H, Furan-H), 6.33 (d, J = 3.0 Hz, 1H, Furan-H), 4.89 (s, 2H, CH2);13C NMR (75 MHz, CDCl3): δ 49.5, 111.4, 112.0, 120.9, 121.4,

RI PT

121.6, 124.2, 126.4, 126.4, 126.5, 126.6, 127.6, 127.8, 127.9, 128.0, 128.3, 128.7, 132.7, 135.0, 143.1, 157.4, 167.4; IR (KBr): υ 758, 1259, 1576, 1710, 2935, 3051 cm-1; ESI-MS: m/z: 548 [M+Na]+. HRMS (ESI) calcd for

(Table

2):

N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(furan-2-yl)-5-

M AN U

4.2.15

SC

C33H23N3O2NaS, 548.1408 [M+Na]+, found: 548.2970.

(naphth alen-2-yl)-3-phenyl-1H-pyrrol-1-yl)acetamide (5o). White solid, mp: 153-155 °C; Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 7.93

TE D

(s, 1H, Ar-H), 7.89-7.74 (m, 3H, Ar-H), 7.59 (d, J = 8.3 Hz, 1H, Ar-H), 7.497.41 (m, 3H, Ar-H), 7.25 (t, J = 6.9 Hz, 4H, Ar-H), 7.14 (t, J = 6.6 Hz, 1 H, ArH), 6.54 (s, 1H, Pyrrole-H), 6.42 (t, J = 3.0 Hz,1H, Furan-H), 6.35 (d, J = 3.2

13

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AC C

CH3);

EP

Hz, 1H, Furan-H), 4.81 (s, 2H, CH2), 3.04 (qt, 2H, CH2), 1.42 (t, J = 7.5 Hz, 3H,

121.3, 125.4, 125.6, 125.8, 126.2, 126.4, 126.4, 126.7, 127.0, 127.4, 127.8, 128.1, 129.0, 129.3, 132.0, 132.7, 135.0, 136.4, 143.7, 144.6, 166.9; IR (KBr): υ 756, 1215, 1340, 1605, 1720, 2926 cm-1; ESI-MS: m/z: 505 [M+H]+; HRMS (ESI) calcd for C30H25N4O2S, 505.16927 [M+H]+, found: 505.16940. 4.2.16 (Table 2): N-benzyl-2-(2-(furan-2-yl)-5-(naphthalen-2-yl)-3-phenyl1H-pyrrol-1-yl)acetamide (5p).

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White solid, m.p: 147-149 °C; Yield: 74%; 1H NMR (300 MHz, CDCl3): δ 7.81 (t, J = 8.3 Hz, 2H, Ar-H), 7.77 (s, 1H) 7.71 (d, J = 3.0 Hz, 1H, Ar-H), 7.48 (t, J = 3.7 Hz, 3H, Ar-H), 7.38 (d, J = 1.5 Hz, 1H, Furan-H), 7.25-7.20 (m, 7H, Ar-H

RI PT

), 7.19-7.12 (m, 2H, Ar-H ), 6.62 (s, 1H, Pyrrole-H ), 6.38 (dd, J = 2.2, 5.2 Hz, 1H, Furan-H), 6.22 (d, J = 3.7 Hz, 1H, Furan-H), 6.06 (t, J = 6.0 Hz, 1H, Ar-H), 4.70 (s, 2H, CH2), 4.45 (d, J = 6.0 Hz, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ

SC

43.3, 49.6, 110.8, 111.2, 112.0, 121.7, 126.3, 126.4, 126.5, 127.4, 127.6, 128.1,

M AN U

128.3, 128.5, 129.0, 132.6, 133.2, 135.1, 136.9, 137.6, 143.0, 144.9, 168.7; IR (KBr): υ 761, 1250, 1543, 1671, 2920, 3062 cm-1; ESI-MS: m/z: 483 [M+H]+. 4.2.17 (Table 2): N-(benzo[d]thiazol-2-(2-(furan-2-yl)-3-(naphthalen-2-yl)-

TE D

5-phenyl-1H-pyrrol-1-yl)acetamide (5q).

White solid, m.p: 119-121°C; Yield: 78%; 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 7.5 Hz, 1H, Ar-H ), 7.55 (d, J = 7.5 Hz, 1H, Ar-H ), 7.45-7.34 (m, 11H,

EP

Ar-H), 7.29 (d, J = 6.7 Hz, 2H, Ar-H ), 6.63 (s, 1H, Pyrrole-H), 6.58 (d, J = 3.0

AC C

Hz, 1H, Furan-H), 6.43 (t, J = 3.0 Hz, 1H, Ar-H), 6.31 (t, J = 3.0 Hz, 1H, FuranH), 6.11 (d, J = 3.7 Hz, 1H, Furan-H), 4.71 (s, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 50.2, 110.1, 111.2, 113.7, 120.9, 121.4, 124.2, 125.4, 125.6, 125.9, 126.2, 126.4, 127.5, 127.9, 128.1, 128.2, 128.9, 131.4, 132.3, 133.4, 133.7, 136.9, 142.0, 148.1, 157.3, 157.4, 167.8; IR (KBr): υ 758, 1270, 1546, 1708, 2923, 3056 cm-1; ESI-MS: m/z: 526 [M+H]+, HRMS (ESI) calcd for C33H24N3O2S, 526.1583 [M+H]+, found: 526.1579.

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4.2.18 (Table 2): N-(5-ethylthiazol-2-yl)-2-(2-(furan-2-yl)-3-(naphthalen-2yl)-5-phenyl-1H-pyrrol-1-yl)acetamide (5r). White solid, m.p: 161-163°C; Yield: 83%; 1H NMR (300 MHz, CDCl3): δ 8.03

RI PT

(d, J = 7.5 Hz, 1H, Ar-H), 7.80 (d, J = 7.5 Hz, 1H, Ar-H), 7.74 (d, J = 3.0 Hz, 1H, Ar-H ), 7.56 (d, J = 6.7 Hz, 2H, Ar-H), 7.45-7.27 (m, 7H, Ar-H), 7.00 (d, J

SC

= 1.5 Hz, 1H, Furan-H), 6.45 (s, 1H, Pyrrole-H), 5.98 (t, J = 3.0 Hz, 1H, FuranH), 5.65. (d, J = 3.0 Hz, 1H, Furan-H), 5.20 (s, 2H, CH2), 3.01 (qt, 2H, CH2),

M AN U

1.40 (t, J = 7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 12.1, 21.3, 46.6, 107.6, 109.5, 110.0, 119.9, 124.0, 124.1, 124.5, 124.8, 124.9, 125.3, 125.6, 125.8, 126.2, 126.5, 127.8, 130.6, 131.3, 133.5, 135.0, 141.4, 141.5, 143.3, 156.2, 164.1, 165.7; IR (KBr): υ 752, 1273, 1550, 1698, 2921, 3056 cm-1; ESI-

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TE D

MS: m/z: 505 [M+H]+, 527 [M+Na]+.

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S6. 1H and 13C NMR Spectrum for compounds 4a-4k & 5a-5r.

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