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Cite this: Org. Biomol. Chem., 2015, 13, 4344
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Novel carbapenem chalcone derivatives: synthesis, cytotoxicity and molecular docking studies† Devendar Reddy Kommidi,*a,b Ramakanth Pagadala,a Surjyakanta Rana,a Parvesh Singh,a Suhas A. Shintre,a N. A. Koorbanally,a Sreekantha B. Jonnalagaddaa and Brenda Moodley*a A one-pot efficient synthetic protocol is described for the synthesis of carbapenem chalcone derivatives using AAPTMS@MCM-41 heterogeneous catalyst. Various substituted aromatic aldehydes were attached to highly chiral and reactive carbapenem using this approach. The cytotoxic activity evaluation of all synthesized compounds was performed against lung cancer cell lines (A-549) and breast cancer cell lines (MCF-7) using the MTT assay. Among the tested compounds, compound CPC-2 showed better activity against MCF-7 cell lines with an IC50 value 2.52 µM mL−1; whereas compound CPC-4 showed good
Received 31st January 2015, Accepted 2nd March 2015
activity against A-549 cell lines with an IC50 value 1.59 µM mL−1. In order to support the observed activity
DOI: 10.1039/c5ob00197h
profiles, the representative compounds were flexibly docked into the active sites of the Anaplastic Lymphoma Kinase (ALK) enzyme and the Estrogen receptor (ERβ). The most active anticancer compounds
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exhibited stronger binding affinities for proteins.
A hybrid approach is a promising way to develop drugs that can target diseases more effectively; these are the compounds with different structures and a variety of biological activities. Novel biological activities can be gained distinct from the ones of the individual components by optimizing properties like affinity and selectivity. A right balance of properties can be achieved through the hybrid approach. Hybrid entities are just like double-edged swords with multiple pharmacophore units.1–3 Most of the clinically used compounds contain β-lactams, and are extensively used as anti-bacterial agents, β-lactamase inhibitors and in other therapeutic areas.4 β-Lactams perform their functions as trans peptidases-and β-lactamase inhibitors. Carbapenem and aztreonam are amongst the β-lactams which can be synthesized, but due to the high chirality and reactive bicyclic ring structure synthetic modification of these compounds is a challenging task. Chalcones are small non-chiral molecules with an α,β-unsaturated carbonyl group. They are the central core of several biologically active compounds exhibiting interesting biological properties like antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and antiinflammatory activities.5–14 Many lead compounds have been
a School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern Hills, Durban 4000, South Africa. E-mail:
[email protected]; Tel: +27 31 260 1099 b Department of Chemistry, Kakatiya University, Warangal, Telangana, India † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c5ob00197h
4344 | Org. Biomol. Chem., 2015, 13, 4344–4350
developed due to their diverse biological properties. For these reasons chalcones have become a tool of choice both in academia and as well as in industry. The biologically diverse properties of β-lactams and chalcones encouraged us towards diamine-functionalized mesoporous silica meditated synthesis, biological investigation and docking studies of carbapenem chalcones derivatives. Review of the literature for chalcone synthesis revealed the use of many techniques and strategies, such as Aldol condensation, Claisen–Schmidt condensation, Suzuki reaction, Witting reaction, Friedel–Crafts acylation with cinnamoyl chloride and Photo–Fries rearrangement of phenyl cinnamates, etc. Among all the available methods Claisen Schmidt condensation is still mostly used. Conventionally, a Claisen– Schmidt condensation reaction is carried out using catalysts like alkaline bases,15 Ba(OH)2,16 and LiOH.17 Recently a new range of catalysts like SOCl2, natural phosphate, lithium nitrate, amino grafted zeolites, zinc oxide, water, Na2CO3, PEG-400, silica sulfuric acid, ZrCl4, mesoporous zirconium phosphate, mesoporous AlSBA-15-SO3H hybrid material, silicotungstic acid, sulfated degussa titania, alkaline-doped carbons, novel solid sulfonic acid from bamboo, aminopropylated silica sol–gel and ionic liquid, etc.,18 were reported for the synthesis of chalcone derivatives. Given the structural variation of our starting material carbapenem there is always scope for the development of a new synthetic strategy. The A ring contributor beta-lactam in the carbapenem part of the hybrid molecule derivatives contains an active methyl keto group and its connection to highly chiral and reactive bicyclic ring structures
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Fig. 2 (A) Small angle XRD pattern of AAPTMS@MCM-41; (B) high angle XRD pattern of AAPTMS@MCM-41 sample. Fig. 1
FT-IR spectrum of AAPTMS@MCM-41.
makes the synthesis interesting. A literature review revealed that amine-functionalized mesoporous silica promotes addition and condensation reactions like Michael and Aldol,19 and these reports encouraged us to synthesize a new catalyst, i.e. diamine-functionalized mesoporus silica (AAPTMS@MCM-41) as the present synthesis proceeds via a Claisen–Schmidt condensation. We successfully employed the catalyst for the present synthesis. Here in we describe the synthesis of carbapenem chalcone derivatives and their efficiency in in vitro anticancer activity against two cancer cell lines using cisplatin as the reference drug. The structure of AAPTMS@MCM-41 was characterized using FT-IR spectroscopy, and its spectrum is shown in Fig. 1. In this spectrum, the band at 1080–1090 cm−1 was due to Si–O starching of Si–O–Si structure. The band at 1620–1640 cm−1 due to H–O–H bending vibration of H2O and 3100–3600 cm−1 for absorption of water molecule.20 The band at 690 cm−1 due to N–H bending vibration and the band at 1532 cm−1 was due to –NH2 symmetric bending vibration. The band at 2935 cm−1 indicating CH2 groups of the propyl chain of the silylating agent of the materials.21 The PXRD patterns of the samples were obtained on a Rigaku D/Max III VC diffractometer with Cu Kα radiation at 40 kV and 40 mA in the range of 2θ = 0–80°. The FE-SEM was performed with a ZEISS 55 microscope. The TEM images were viewed on a Jeol JEM-1010 electron microscope. The small angle and high angle XRD patterns of AAPTMS@MCM-41 are shown in Fig. 2A and 2B. This material displays a strong peak at 2θ = 2.2° due to (100) plane and also the small peaks indicate the formation of well-ordered mesoporous materials due to higher order (110), (200) and (210) plane reflections within 5°. There was only a small reduction of the (100) peak. So, the mesoporosity remains unchanged after the modification of the silica network by both organo groups. The high angle XRD spectrum shows (Fig. 2B) only dispersion of the organic group in a non-crystalline form on the surface of MCM-41.
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Fig. 3
SEM image of AAPTMS@MCM-41 sample.
Fig. 4
EDX spectrum of AAPTMS@MCM-41 sample.
The scanning electron microscope image of AAPTMS@ MCM-41 is shown in the Fig. 3. This image shows a slightly elliptical morphology. Thus it was confirmed that the particles are well ordered after modification of the organic group on the support surface parent material. The EDX spectrum (Fig. 4) gives information about the AAPTMS@MCM-41 sample. This image shows that only N, Si, C and O are present in this material. The transmittance electron microscope (TEM) image of AAPTMS@MCM-41 (Fig. 5) confirmed that after modification
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Organic & Biomolecular Chemistry Table 2
Entry
Catalyst
Time (h)
Yielda (%)
1 2 3 4 5
Fresh 2nd run 3rd run 4th run 5th run
2.0 2.0 2.0 2.0 2.0
90.0 90.0 88.0 85.0 75.0
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a
Fig. 5
Recyclability of AAPTMS@MCM-41 tested for compound 5a
Isolated yields.
TEM image of AAPTMS@MCM-41.
Table 1
Optimization of reaction conditionsa
Entry
Catalyst
Amount
Solvent
Time (h)
Yieldc (%)
1 2 3 4 5 6 7 8 9 10
NaOH NaOH KOH KOH SSAb SSA Ba(OH)2 Ba(OH)2 Catalystd Catalystd
— —
EtOH–H2O ACN EtOH–H2O ACN EtOH–H2O ACN EtOH–H2O ACN EtOH–H2O ACN
9 9 9 9 9 9 9 9 9 8 min
20 30 25 35 20 25 15 20 60 92
—
a
Note: Reactions performed at room temperature (27 °C ± 3). Silica Sulfuric Acid. c Isolated yields. d AAPTMS@MCM-41.
Table 3
b
SSA:
the materials exhibit well-ordered elliptical morphology. The high magnification image shows that the material has a porous nature. Optimization of reaction conditions and identification of the best base catalyst were achieved by varying the chosen catalysts and solvents successively (Scheme 2). Initially the reaction between carbapenem and substituted aryl aldehydes was examined using conventional catalysts like KOH–EtOH, NaOH–EtOH, silica sulphuric acid and Ba(OH)2. Having failed to obtain the desired products in good yields we employed base catalyst AAPTMS@MCM-41 and obtained the desired products in more than 90% yield within less than 10 minutes of reaction time (Table 1). The basic cites in catalyst AAPTMS@MCM-41 helped the condensation between active methyl groups of carbapenem and substituted aromatic aldehydes (Scheme 2). The catalyst was recovered by simple filtration. Activity of the catalyst was retained up to the 5th cycle. Studies with recycled catalyst showed that it can be reused at least four times with no significant loss (