J . Chem. Tech. Biotechnol. 1992,53, 329-336
Synthesis and Antibacterial Activity of Certain Quinoline and Quinazoline Derivatives Containing Sulfide and Sulfone Moieties7 Maher F. El-Zohry,*" Abd El-Hamed N. Ahmed,b Farghaly A. Omarb & Mohamed A. Abd-Alla" "Department of Chemistry, Faculty of Science, bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 7 1516, Egypt (Received 7 May 1991 ; revised version received 15 August 1991 ; accepted 23 October 1991)
Abstract : Some aryl and/or heterocyclic mercaptans were allowed to react with 8-quinolyl chloroacetate (11), 8-quinolinoxyacetyl chloride (IV) and 3-(2'-chloroethyl)-2-methyl-3,4-dihydroquinazolin-4-one(X) in dry benzene and/or sodium hydroxide in absolute ethanol to give corresponding 8-quinolyl-amercaptoacetate (V), 8-quinolinoxythioacetate(VI) and 3-(2'-arylmercaptoethy1)2-methyl-4-(3H)quinazolin-4-onesor 3-(2'-heterocyclicmercaptoethyl)-2-methyl4(3H)-quinazolin-4-ones (XIa-h). The mercaptans V and XI were subjected to oxidation with hydrogen peroxide/acetic acid mixture (1 :2) to afford the corresponding sulfones VII and XII. The structures of the synthesized compounds were elucidated by spectroscopic (IR and 'H-NMR) and elemental analyses. Some of these compounds were tested for their antimicrobial activities in comparison with tetracycline as a reference compound.
Key words : quinoline, quinazoline derivatives, antibacterial activity, sulfides, sulfones
drugs of proven therapeutic importance and used against a wide spectrum of bacterial ailments."-16 Diverse biological activities have been encountered in 8-Hydroxyquinoline and its derivatives are reported as compounds having the quinazoline ring ~ y s t e m . l ~In- ~ ~ well known antimicrobial agent~.l-~ In many cases the previous work, the synthesis and antimicrobial activities antimicrobial activity of 8-hydroxyquinoline derivatives of certain quinazolines containing pep tide^,^^ salicylic has been attributed to the chelating properties provided by the 8-hydroxyl group and the quinoline ring n i t r ~ g e n . ~ acid,39 sulfa drug moieties,*' and oxadiazolin-5-thione rnoieties4l have been described. From this point of view Some metal complexes of 8-hydroxyquinoline have been it was very interesting to synthesize some 8-quinolyl-astudied due to their established biological activities.'-'' mercaptoacetates (V), 8-quinolinoxythioacetate derivThe most commonly known bactericidal 8-hydroxyatives (VI) and 8-quinolyl-a-sulfonylacetates (VII) with quinoiine derivatives were obtained through ring substitution, for example 5,7-dichloro-8-hydroxyquinoline the aim of investigating their antimicrobial potency with (Haloquinol INN), 5-chloro-8-hydroxy-7-iodoquinoline special reference to the starting 8-hydroxyquinoline. The (Clioquinol) and 8-hydroxy-7-iodo-6-quinolinesulfonic effect of the side chain variation, as ester and ether, upon the antimicrobial action will also be discussed. acid (Chiniofon).' Also it was very interesting to synthesize a new series Furthermore some sulfur-containing compounds are of quinazoline derivatives containing sulfides and sulfones with the aim that the incorporation of a quinazoline moiety with aryl and/or heterocyclic mercaptans may * To whom correspondence should be addressed. play a significant role in improving the antimicrobial t Accepted and orally presented at AAPS, Nov. 4-9, 1990, Las activity. Vegas, USA. 329 25-2 INTRODUCTION
M . F. El-Zohry et al.
330 EXPERIMENTAL The time required for completion of the reaction was monitored by thin layer chromatography (TLC). Melting points were determined in open glass capillaries and are uncorrected. IR-spectra were recorded on a Pye-Unicam SP 200G spectrophotometer. 'H-NMR spectra were measured in dimethyl sulfoxide-d, or trifluoroacetic acid using TMS as internal standard on EM 360 90 MHz NMR spectrophotometer. Microanalyses were determined on a Perkin-Elmer 240 C microanalyser. 8-Quinolyl-a-chloroacetate (II)" In a two-necked round bottomed flask (250 ml) fitted with a reflux condenser and a 50ml dropping funnel, 5.8 g (0.04 mole) 8-hydroxyquinoline was dissolved in 100 ml dry pyridine. To the stirred solution there was added dropwise 2.0 ml (2.5 g, 0-022 mole) of freshly distilled chloroacetyl chloride. The reaction mixture was then stirred for 2 h at room temperature and then filtered. The golden yellow precipitate was crystallized from petroleum ether (60-8OoC), m.p. 21 8-220°C.
8-Quinolinoxyacetyl chloride (IV)4394-1 A solution of 2.46 g (0.044 mole) of potassium hydroxide in 100ml absolute ethanol was prepared. To this
solution, 3.1 g (0.022 mole) of 8-hydroxyquinoline was added, then 2.5 g (0026 mole) of chloroacetic acid was added portionwise. The solution was refluxed with stirring for 20 h. After cooling to room temperature the reaction mixture was acidified by 5 ml of conc. HCl, and filtered to remove the precipitated KCI. The ethanol was removed under reduced pressure to afford the corresponding acid which was converted to the acid chloride by treatment with 2.5 ml of thionyl chloride in 50 ml dry benzene and subsequent reflux for 1 h. The solvent and excess thionyl chloride were removed by distillation under reduced pressure. The residual acid chloride was crystallized from petroleum ether (6O-8O0C), then was used for synthesis of the thioacetate derivatives VIa-e.
Reaction of 8-chloroacetoxyquinolineand/or 8quinoloxyacetyl chloride with aryl(heterocyc1ic)mercaptans A 0.01 mole amount of 8-chloroacetoxyquinoline (11) and/or 8-quinoloxyacetyl chloride (111) was dissolved in 25 ml dry benzene. To this solution 0.01 mole of the aryl(heterocyc1ic)mercaptan was added portionwise and the mixture was refluxed for 8 h. Benzene was removed under reduced pressure and the product was crystallized from the appropriate solvent (Tables 1 and 2).
TABLE 1 Physical Properties, Yields and Elemental Analyses of the 8-quinolyl-a-mercapto(sulfonyl)acetateDerivatives (V, VII) Compound
Yield (YO)
X
m.p.
("c)
Microanalyses-Calcdl found (YO)
Molecular formula C
H
N
s
CI
~
Va
73
220-2"
Vb
72
245"
vc
65
140-2'
Vd
72
210-12c
Ve
63
1 70b
VIIa
70
80-2"
VIIb
73
624"
VIIC
73
120-2"
VIId
75
60-3"
69-90 69-50 62-02 62.30 61.36 61.20 64.67 . 64.50
C18H1304N3S
(366) 65
VIIe
115-17d
C14H1104N3S
(3 17) Ethanol/water.
' Ethanol.
l1
Methanol. Methanollwater.
58.94 58.50 63.34 63.30 56.50 5630 56.25 56.70 59.01 58.50 52.95 5220
4.85 4.80 3.64 3.50 3.40 3.40 3.59 3.20 3.85 3.70 4.30 4.18 3.30 3.20 3.10 2.50 3.24 3.10 3.40 3.10
4.53 4.30 425 4.20 7.95 7.80 12.59 12.40 14'73 14.40 4.12 3.90 3.87 3.40 7.29 7.90 11.47 11.20 13.20 12.99
10.35 10.50 9.72 10.00 18.18 18.50 9.58 9.30 11.22 11.30 9.38 8.60 8.80 8.30 16.60 16.40 8.70 8.21 10'09 9.70
-
-
10.6 10.6 -
-
-
-
-
Properties of quinoline and quinazoline derivatives
331
TABLE 2 Physical Properties, Yields and Elemental Analysis of 8-quinolinoxythioacetate Derivatives (VIa-e)
Compound
X
Yield (YO)
m.p.
(“0
Mieroanalyses-Calcd/found (YO)
Molecular formula
VIa
S
83
2 15-7“
VIb
S
73
230-2”
VIC
S
65
260-2“
VIQ
S
72
190-2“
C18H1202N3S
VIe
S
63
160-lb
C14H110ZN3S
~,,Hl,OZNS (309) Cl,H12C10zNS (329) Cl8H12O2NZS2 (352) (334) (285)
Oxidation of 2’-Aryl(heterocyclic)mercapto-8acetoxyquinoline (Va-e) (general procedure)
2’-Aryl(heterocyclic)mercapto-8-acetoxyquinoline (0-01 mole) was dissolved in glacial acetic acid, then the calculated volume of hydrogen peroxide (30 YO)was added dropwise. The reaction mixture was left to stand for 3 days at room temperature, then the combined solvents were removed and the products VIIa-e were crystallized from the appropriate solvents (Table 1). Preparation of 3-(2’-hydroxyethyl)-2-methyl-3,4dihydraquinazolin-4-one (IX) and 3-(2’-chloroethyl)-2methyl-3,4-dihydroquinazolin-4-one(X) These compounds were synthesized according to the reported procedure^.^^ Synthesis of 3-(aryl(heterocyclic)mercaptoethyl)-2methyl-3,4dihydroquinazolin-4-ones (XIa-h) A solution of 0.025 mole of the aryl mercaptan and/or heterocyclic mercaptan was added to 0.025 mole of X in 50 ml ethanol containing 0.025 mole sodium hydroxide. The reaction mixture was refluxed on a water bath for 4 h, then cooled to room temperature while the desired product precipitated. The product was filtered off, washed with cold water, dried and crystallized from the appropriate solvent. Physical properties of compounds XIa-h are depicted in Tables 3 and 4. Synthesis of 3-(aryl(heterocyclic)sulfonyIethyl)-2-methyl3,4-dihydroquinazolin-4-ones (XIIa-h) A solution of 0001 mole of XIa-h was dissolved in 20 ml of AcOH, to this solution there was added 10ml of H,O,. The reaction mixture was warmed on a water bath at 70°C for 3 h, then cooled to room temperature,
C
H
N
S
69.90 69.61 62.02 62.50 61.36 61.10 64.67 64.30 58.94 58.60
4.85 4.70 3.64 3.40 3.40 3.21 3.59 3.30 3.85 3.60
4.53 4.41 4,25 4.25 7.95 7.70 12.57 12.30 14.73 1400
10.35 1020 9.72 9.50 18.18 18.20 9.58 9.20 11.22 11.10
Cl
whereby the desired sulfones XIIa-h were precipitated, filtered off, dried and crystallized from the appropriate solvent. Physical properties of XIIa-h are shown in Tables 3 and 4. RESULTS AND DISCUSSION The reaction of 8-hydroxyquinoline (I) with chloroacetyl chloride in pyridine proceeds very smoothly at room temperature giving 8-quinolyl-a-chloroacetate (11) in good yields. The reaction of compound I1 with the appropriate aryl and/or heterocyclic mercaptans afforded the 8-quinolylesters (Va-e) (Scheme 1). Physical constants, yields and elemental analyses of compounds Va-e are presented in Table 1. 8-Quinolinoxythioacetates (VIa-e) were also obtained by the interaction of the same series of aryl and/or heterocyclic mercaptans and 8-quinolinoxyacetyl chloride (IV) under the same conditions in boiling benzene. The latter intermediate (IV) was readily accessible through reaction of 8-hydroxyquinoline with chloroacetic acid followed by treatment of the 8-quinolinoxyacetic acid (111) produced with thionyl chloride in dry benzene. The physical constants, yields and elemental analyses of the 8-quinolinoxythioacetate derivatives (VIa-e) are summarized in Table 2. The 8-quinolyl-a-mercaptoacetate derivatives Va-e were subjected to oxidation to explore the effect of this type of sulfur linkage, in the side chain, on the antibacterial activity. Sulfones (VII), were obtained by the oxidation of the corresponding mercapto derivatives (Va-e) with hydrogen peroxide in glacial acetic acid at room temperature. The yields, physical constants and elemental analysis of compounds VIIa-e are shown in Table 1. The IR-spectra of the 8-quinolylacetate derivatives (Va-e) show a characteristic strong absorption band at
M . F. El-Zohry et al.
332
TABLE 3 Physical Properties of 3-(2’-aryl(heterocyclic)mercaptoethyl)-2-methyl-3,4-dihydroquinazolin-4-one (XIa-h) and 3-(2-aryl(heterocyclic)sulfonylethyl)-2-methyl-3,4-dihydroquinazolin-4-one(XIIa-h) Compound
Solvent of crystallization
m.p.
Yield
(“C)
(%I
Molecular formula
Analysis calcd (found) (YO) C
H
N
XIa
Ethanol
18&2
82
C,,H,,ON,S
68.91 (68.87)
5.40 (5.36)
9.45 (9.72)
XIb
Ethanol
24&2
87
C,,H,,ON,S
69.67 (69.71)
5-80 (5.71)
9.03 (9.10)
XIC
Ethanolwater (1 : 1)
200-2
81
C,,H,,ON,SCl
61.81 (61.85)
4.54 (4.51)
8.48 (8.79)
Xld
Ethanolwater (1 : 1)
300-2
79
C,,H,,ON,S
69.67 (69.70)
5.80 (5.71)
9.03 (9.32)
XIe
Ethanol
300-2
72
C,,H,,ON,S
72.83 (72.61)
5.20 (5.19)
8.09 (8.00)
XIf
Ethanolwater (1 : 1)
28&2
86
C,,H,,ON,S
58-74 (58.96)
4.89 19-59 (4.82) (19.56)
Xk
Ethanol
11&12
76
C,,H,,ON,S,
61.18 (61.49)
424 (418)
11.89 (12.18)
XIh
Methanol
85-7
69
C,,H,,ON,S
64.28 (64.22)
4.76 (468)
16.60 (16.56)
Xlla
Ethanol
190-2
87
C,,H,,O,N,S
62.19 487 (62.26) (4.66)
8.53 (842)
XIIb
Ethanolwater (1 : 1)
11@1-2
85
C,,H,,O,N,S
63.15 (63.46)
526 (5.20)
(8-12)
XIIC
Ethanol
160-2
81
C,,H,,O,N,SCI
56.35 (56.31)
4.14 (4.31)
7-73 (7-65)
XIId
Waterethanol (2: 1)
245
81
C,,H,,O,N,S
63.15 (63.31)
5.26 (5.20)
(8.12)
XIIe
Methanol
300
67
C,,H,,O,N,S
66.66 (66.72)
4.76 (459)
7-40 (7-32)
XIIg
Methanol
18&2
81
C,,H,,O,N,S,
5610 (56.20)
3.89 (3.75)
10.90 (10.95)
XIIh
Methanol
110-12
78
c,,H,,o,N,s
58.69 (58.57)
4-34 (469)
15.21 (15.30)
8.18
8.18
IR (KBr), cm-l
S
10.81 3040 (CH arom), 2920 (10.71) (CH aliph), 1680 (C=O), 1600 (C=N inside the ring), 700 (C-S) 10.32 3045 (CH arom), 2927 (10.27) (CH aliph), 1690 (C=O), 1610 (C=N), 710 (C-S) 9-69 3025 (CH arom), 2930 (9.58) (CH aliph), 1700 (C=O), 1605 (C=N), 800 (C-Cl), 695 (C-S) 10.32 3010 (CH arom), 2900 (1047) (CH aliph), 1690 (C=O), 1600 (C=N), 700 (C-S) 9.24 3020 (CH arom), 2950 (9.57) (CH aliph), 1705 (C=O), 1650 (C=N), 695 (C-S) 11.18 3400 (NH), 3010 (CH arom), (I 1.10) 2970 (CH aliph), 1710 (CEO), 1690 (C=N), 690 (C-S) 1813 3015 (CH arom), 2980 (18.06) (CH aliph), 1700 (C=O), 1680 (C=N), 700 (C-S) 9.52 3445 (NH), 3050 (CH arom), (949) 3000 (CH aliph), 1710 (C=O), 1600 (C=N), 700 (C-S) 975 3040 (CH arom), 2930 (CH (9-91) aliph), 1700 (C=O), 1620 (C=N), 1400 (SO,), 700 (C-S) 9.35 3045 (CH arom), 2930 (CH (9.31) aliph), 1700 (C=O), 1675 (C=N), 1420 (SO,), 710 (C-S) 8.83 3020 (CH arom), 2950 (CH (8.62) aliph), 1690 (C=O), 1620 (C=N), 1420 (SO,), 800 (C-Cl), 700 (C-S) 9.35 3040 (CH arom), 3000 (CH (9.61) aliph), 1700 (C=O), 1650 (C=N), 1410 (SO,), 700 (C-S) 8.46 3055 (CH arom), 2900 (CH (8.61) aliph), 1710 (C=O), 1640 (C=N), 1420 (SO,), 700 (C-S) 16.62 3050 (CH arom), 2970 (16.51) (CH aliph), 1705 (CEO), 1685 (C=N), 1420 (SO,), 700 (C-S) 8.69 3455 (NH), 3050 (CH (8.89) arom), 2990 (CH aliph), 1700 (C=O), 1630 (C=N), 1380 (SO,), 695 (C-S)
Properties of quinoline and quinazoline derivatives
333 TABLE 4
'H-NMRData of 3-(2'-aryl(heterocyclic)meracptoethyl)-2-methyl-3,4-dihydroquinqzolin-4-one (XIb, e) and 3-(2'-aryl(heterocyclic)sulfonylethyl)-2-methyl-3,4-dihydroquinazolin-4-one(XIIa, b, c, e) 'H-NMR (solvent), G(TMS) pprn
Compound
(DMSO.d,) 25 (3H,S), 3.0 (3H,S), 3.8-4.0 (2H,t), 4.3-45(2H,t), 7.5-7.71(4H,m), 7.9-8 (2H,d), 8.1-8.3(2H,d) (CF,COOH)3.2 (3H,S), 4.M.1(2H,t), 4.5-4.7(2H,t), 7.5-7.8(4H, m), 7.95 (2H,d), 8.3-8.4(2H,d) (CDCl,/CF,COOH) 2.4(3H,S), 3.9(2H,,)t 4.3 (2H,t), 7.3-8.0(8H,m), 8.3(2H,d) (CDCl,/DMSO.d,) 2.6 (3H,S), 3.6 (2H,t), 4.4(2H,t), 7.2-7.6 (5H,m), 7.8 (2H,d), 79-8.1 (2H,d) m), 7.9-8.0(2H,d), 8.1-8.3(2H,d) (DMSO.d,) 2.6 (3H,S), 3.0(3H,S), 3.84.0(2H,t), 4.345 (2H,t), 75-7.7 (4H, (DMSO.d,)/CF,COOH) 3-1(3H,S), 4-3(2H,t), 4.5-4.7(2H,t), 7.6-7.8 (4H, m), 7-9(2H,d), 8-3-8.4(2H,d) (DMSO.d,/CF,COOH) 26 (3H,S), 3.9(2H, t), 4.3 (2H,t ) , 76-8.0 (8H,m), 8.3 (2H,d)
XIb XIC XIe XIIa XIIb XIIC XIIe
~
~ ~ r ~ ~ ~ e c l
ArSH
H202/AcoH
25" C
OCOCH,CI
OCOCH,SAr
II
OCOH2S0,Ar
Vlla-e
Va-e
OH I
\(1)c1CH2coo~
NaOH/ethanol (2) dil. HCI N
ArSH
eb::::
' OCH,COOH
I
OCH,COCI
111
OCH,COSAr
IV
Vla-e
H
H
Scheme 1
1 7 3 ~ ~cm-l 4 0 corresponding to the stretching vibrations of C=O group in the ester function. It was observed that substitution at the a-position of the side chain does not considerably influence the frequency of this carbonyl vibration. Also when the a-positioned sulfur atom was oxidized to the corresponding sulfone function to afford compounds VIIa-e, there was no observable change in the frequency of the carbonyl ester in comparison with the parent compounds Va-e. The a-sulfonyl derivatives are characterized furthermore by the appearance of a new band at 1410 cm-' corresponding with the -SO, group. In the 8-quinolinoxythioacetate derivatives (VIa-e) the frequency of the carbonyl group is generally lowered to 1700-1690 cm-I due to the presence of the sulfur atom in the ester moiety instead of oxygen. 'H-NMR spectra were taken in trifluoroacetic acid for some of the synthesized compounds. The general feature
-
for all derivatives is the presence of the singlet, integrated for 2H, in the range between 63.9 and 35ppm. The aromatic protons appear as a complex system in the range between 67.8 and 9.3 ppm. Some signals could be identified such as that at 69.4 ppm (1H) with characteristic ortho coupling (- 5 Hz), this signal was assigned to H-2 of the quinoline ring. Its downfield shift with respect to the other protons is due to the ring nitrogen. The triplet at 69.2 ppm, integrated for 2H, is assigned to H-3 and H-6 of the quinoline nucleus. The splitting pattern of this signal is attributed to the two ortho protons H-2/H-4 and/or H-5/H-7. The other aromatic protons of the side chain substituent appear in the range between 7.2 and 8-0 ppm. Going to the synthesis of quinazolin-4-one derivatives, our precursor 2-methyl-(3,l)-benzoxazin-4-one(VIII) was allowed to react with ethanolamine to afford the
M . F. El-Zohry et al.
334
R
0
X
IX
Vlll
9
9 AcOH ~ ~
- &4rH2CHzSOzAr 0 ,
NaOH/ ethanol
CH3
XI1 a-h
XI a-h
H Scheme 2
corresponding alcohol (IX). The reaction of IX with thionyl chloride gave the corresponding chloro derivatives X. The reaction of X with aryl mercaptans and/or heterocyclic mercaptans in sodium hydroxide yielded 3-(2'-arylmercaptoethyl)-2-methyl-4-(3H)quinazolin-4-ones and/or 3-(2'-heterocyclic mercaptoethy1)-2methyl-4(3H)quinazolin-4-ones (XIa-h). Oxidation of compounds XI using hydrogen peroxide in acetic acid, gave the corresponding sulfones XIIa-h (Scheme 2). The structure assignment of the prepared compounds XIa-h and XIIa-h was elucidated by their elemental and spectral analyses (cf. Tables 3 and 4). Antimicrobial Activity The antibacterial activity of the newly synthesized compounds was tested against the following organisms : Gram-positive-Staphylococcus aureus ATCC 25923, NCTC 6571, DSM 1104; Gram-negative-Escherichia coli ATCC 25823, NCTC 1048, DSM 10. Agar cup diffusion techniques were used and tetracycline HCl was used as a standard reference. The synthesized compounds Va-e, VIa-e and VIIIa-e were tested for their antimicrobial activity using agar cup diffusion techniques.*' Their minimum inhibitory concentration (MIC) was calculated @g 1-l) against Staphylococcus aureus and Escherichia coli. This method
depends on the diffusion of the drug tested from cylinders or from wells placed on the surface of seeded agar. As the plate is incubated, the drug diffuses into the medium giving zones of progressively lower concentration, The test organism can grow up to the zone on minimum inhibitory concentration but not inside it. For determination of MIC of the tested compounds five different concentrations of each compound (5, 2.5, 1.25,0.625,031 pg) in 1 ml DMSO were prepared under sterile conditions and transferred to the appropriate wells in the preinoculated agar plates. Five equivalent concentrations of 8-hydroxyquinoline were also prepared and tested against the same microorganisms. After incubation of the petri dishes at 37°C for 48 h, the diameter of inhibition zones for each concentration of the considered compounds were measured. The MIC values were then calculated mathematically according to the linear regression equation : Y=a+bX where Y = square of the diameter of inhibition zone in mm;
X = log concentration in ,ug ml-'; a = constant value corresponding to the intercept;
b = slope of the linear regression line; a/b = log MIC.
Properties of quinoline and quinazoline derivatives
TABLE 5 MIC (pg ml-l) Compound
Va Vb vc Vd Ve 111 I
VIa VIb VIC VId VIe Tetracycline
MIC" (correlation coeficient)
E. coli
S. aureus
10.7 (098) 3.1 (0966) 3.8 (0.989) 1.4 (0930) 1.4 (0.98) 4.6 (0.673) 9.6 (0.959) 4.4 (0.978) 3.1 (0.945) Inactive 3.8 (0.989) 3.9 (0.991) 3.6 (0.99)
18.2 (0.991) 10.5 (0.986) 2.7 (0945) 1.9 (0.997) 1.9 (0.99) 4.1 (0.614) 4.0 (0,992) 2.1 (0.981) 2.8 (0.981) Inactive 4.3 (0.999) 3.4 (0,974) 4.0 (0.99)
Table 5 gives the calculated MIC values ,ug 1-' for the tested compounds with their corresponding correlation coefficients. From the analysis of the MIC data given in Table 5, it was observed that the thioacetate derivatives VIa-e exhibit higher antimicrobial activities than the corresponding a-mercaptoacetates (Va-e) and also higher than the starting 8-hydroxyquinoline (I) and its 8quinolineoxyacetic acid (111). Oxidation of the sulfur linkage in the side chain of mercaptoacetate derivatives Va-e to their corresponding TABLE 6 Molar Minimum Inhibitory Concentration (MIC pg ml-l) Compound
XIa XIb XIC XId XIe XIf XI&! XIh XIIa XIIb XIIc XIId XIIe XIIf XIIg XIIh Tetracycline
MIC (pg ml-')
E. coli
S. aureus
Inactive Inactive 050 ( r = 0.99) 060 ( r = 0.98) 0.30 (r = 0.99) Inactive Inactive Inactive Inactive 0 2 0 (r = 098) 0.40 ( r = 0.99) 0.30 ( r = 098) Inactive Inactive Inactive Inactive 0.35 ( r = 0.99)
Inactive Inactive Inactive Inactive Inactive Inactive Inactive Inactive Inactive Inactive 0.30 (0.99) 0.40 (0.98) Inactive Inactive Inactive Inactive 038 (0.99)
335
sulfones VIIa-e abolished the antimicrobial activity. Within the series of 8-quinolyl-a-mercaptoacetate (Va-e), it was found that the side chain bearing heterocyclic moiety as compounds Vd and Ve showed higher antimicrobial activity than those with an aryl substituent (Va, Vb and Vc). For the 8-quinolinoxythioacetate derivatives (VIa-e), most of the tested compounds showed generalized activity against the S. aureus and E. coli bacteria species tested but VIa and VIb showed higher activity against S. aureus than did VId and VIe. Within the series of quinazoline derivatives containing sulfide moiety, the compounds which showed the most potent inhibition of E. coli were the compounds having the chlorophenyl (XIc), benzyl (XId) and naphthy1 moiety (XIe). For the quinazoline derivatives containing the sulfone moiety, XIIb showed high activity against E. coli while XIIc and XIId showed a generalized activity against S. aureus and E. coli bacteria species tested relative to tetracycline. Table 6 shows the MIC (ug ml-') values for the tested compounds XIa-h and XIIa-h.
REFERENCES 1. Tadeusz, F. M. & John, D. F., Tetrahedron Lett., 29(18) (1988) 2137. 2. Khalil, Z. H., Yanni, A. S., Abdel-Hafez, A. A. & Khaiaf, A. A., J. Indian Chem. Soc., 64(1) (1987) 42. 3. Sharada, J., Ratna, Y. K. & Kanakalingeswara, R. M., Indian J. Pharm. Sci., 49(1) (1987) 17. 4. Abdel-Hadi, A. Z., Zayed, S., Herb, A. A. & Manhi, F. M., Pol. J . Pharmacol Pharm., 38(1) (1986) 99. 5. Swhunack, W., Mayen, K. & Haake, M., In Arzneistofe, Lehrbuch der Pharmazeutische Chemie, 2 Aufl. Vieweg Verlag, Braunschweig, 1984, p. 533. 6. Proffit, E. & Buchmann, G., Arzneimittel-Forsch., 10 (1960) 181. 7. Nishihara, H., J. Biol. Chem. Jpn, 40 (1953) 579. 8. Williams, D. R., Chem. Rev., 72 (1972) 203. 9. Ibrahim, S.A., Makhlouf, M. Th., Abdel-Hafez, A. A. & Moharram, A. M., J. Inorg. Biochem., 28 (1986) 57. 10. Ghoneim, K. M., Osman, A. N., Said, M. & El-Keroch, T. A., Egypt. J . Pharm. Sci., 28 (1987) 17. 11. Chaurosia, M. R., Sharma, S. K. & Kumar, R., Indian J . Pharm. Sci., (1979) 152. 12. Snyder, H. R., Jr & Benjamin, L., J. Med. Chem., 13 (1970) 164. 13. Shimidzu, N. & Uno, T., Chem. Pharm. Bull., 26 (1978) 127. 14. Clayson, D. B., Pringle, J. A. S.& Ranses, G. M., Biochem. Pharmacol., 16 (1967) 614. 15. Beerlev, W. N., Peters, W. & Mayer, K., Ann. Trop. Med. Parasitol., 62 (1960) 288. 16. Tarbini, G., Proc. 5th Inst. Congr. Chemother., 2 (1967) 909. 17. Armarego, W. L. F., Advan. Heterocyclic Chem., 1 (1963) 253. 18. Baker, B. R., Schaub, R. E., McEvoy, F. J. & Williams, H. H., J. Org. Chem., 17 (1952) 132. 19. Ablondi, F., Gordon, S., Morton, J. & Williams, J. H., J. Org. Chem., 17 (1952) 19.
M . F. El-Zohry et al. 20. Camrridge, A. B., Jansen, A. & Jarman, D. A., Nature, 1% (1962) 1217. 21. Amin, A. H., Mehta, D. R. & Samrth, S. S., Proc. 1st Intern. Pharmacol. Meeting, Stockholm, 7 (1961) 371. 22. Gujral, M. L., Sareen, K. N. & Kohli, R. P. J., Med. Res., 145 (1957) 207. 23. Bianci, C. & David, A. J., Pharm. Pharmacol., 12 (1960) 501. 24. Boltz, K. H., Dell, H. D., Lehwald, H., Lorenz, D. & Aubert, M. Schweer, Arzneimittel-Forsch, 13 (1962) 688. 25. Petersen, S., Herlinger, H., Tietze, E. & Siefken, W., Angew Chem., 74 (1962) 855. 26. Revina, A., Presse Med., 67 (1959) 891. 27. Destevens, G., Diuretics. Academic Press Inc., New York, 1963, p. 112. 28. Leskovszky, G., Erdely, I. & Tardos, L., Acta Physiol. Acad. Sci. Hung., 27 (1964) 81. 29. Deysson, G. & Truhaunt, R., Ann. Pharm. France, 23 (1965) 229. 30. Maucevic, G., Stotzer, H. & Wick, H., ArzneimittelForsch., 15 (1965) 613. 31. Hsyao, S., Havera, H. J., Strycker, W. G., Leipzig, T. J., Kulp, R. A. & Hartzier, H. E., J. Med. Chem., 8 (1965) 807. 32. Kozhennikov, Yu. V., IZV. Vyssh. Ucheb. Zaved., a i m . Tekhol., 14 (1971) 1959; Chem. Abst., 77 (1972) 19599 P.
33. Buzas, A. & Hoffman, C., Bull. SOC.Cheim. France, 26 (1959) 1889. 34. Somasekhara, S., Dighe, V. S., Mankad, P. R. & Mukherjee, F. A., Indian J. Chem., 2 (1964) 369. 35. Dighe, V. S., Somasekhara, S., Bagabant, G. & Mukherjee, S. L., Current Sci. (Indian), 33 (1964) 78. 36. Peck, R. M., Connel, A. P. 0. & Creech, H. J., J. Med. Chem., 9 (1966) 217. 37. Preton, R. K., Peck, R. M., Breuninger, E. R., Miller, A. J. & Creech, H. J., J. Med. Chem., 7 (1964) 471. 38. El-Khawaga, A. M., Abd-Alla, M. A. & Khalaf, A. A., Gazzetta Chimica Italian, 111 (1981) 44-2. 39. Abd-Alla, M. A., Yanni, A. S., Ahmed, S. H. & AbdelRaheam, M. H., Bull. Pharm. Sci., Assiut University, 7 (1984) 22436. 40. Yanni, A. S. 81 Abd-Alla, M. A., Bull. Fac. Sci., Assiut University, 16 (1987) 55-9. 41. Ahmed, A. N., Abd-Alla, M. A. & El-Zohry, M. F., J. Chem. Tech. Biotechnol., 43 (1988) 63-70. 42. Behera, B., Rath, P. C. & Rout, M. K., J. Indian Chem. Soc., 44 (1967) 119-22. 43. Nagel, O., Monatsh. Chem., 18 (1897) 32. 44. Rasshofer, Mueller, W. M. & Voegtle, F., Chem. Ber., 112 (1979) 2095-119. 45. Singh, P., J. Indian Chem. Soc., IV (1978) 801-5. 46. Collins, C. H., Microbiological Methods. Butterworths, London, 1964, p. 92.
Synthesis and Antibacterial Activity of Certain Quinoline and Quinazoline Derivatives Containing Sulfide and Sulfone Moieties7 Maher F. El-Zohry,*" Abd El-Hamed N. Ahmed,b Farghaly A. Omarb & Mohamed A. Abd-Alla" "Department of Chemistry, Faculty of Science, bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 7 1516, Egypt (Received 7 May 1991 ; revised version received 15 August 1991 ; accepted 23 October 1991)
Abstract : Some aryl and/or heterocyclic mercaptans were allowed to react with 8-quinolyl chloroacetate (11), 8-quinolinoxyacetyl chloride (IV) and 3-(2'-chloroethyl)-2-methyl-3,4-dihydroquinazolin-4-one(X) in dry benzene and/or sodium hydroxide in absolute ethanol to give corresponding 8-quinolyl-amercaptoacetate (V), 8-quinolinoxythioacetate(VI) and 3-(2'-arylmercaptoethy1)2-methyl-4-(3H)quinazolin-4-onesor 3-(2'-heterocyclicmercaptoethyl)-2-methyl4(3H)-quinazolin-4-ones (XIa-h). The mercaptans V and XI were subjected to oxidation with hydrogen peroxide/acetic acid mixture (1 :2) to afford the corresponding sulfones VII and XII. The structures of the synthesized compounds were elucidated by spectroscopic (IR and 'H-NMR) and elemental analyses. Some of these compounds were tested for their antimicrobial activities in comparison with tetracycline as a reference compound.
Key words : quinoline, quinazoline derivatives, antibacterial activity, sulfides, sulfones
drugs of proven therapeutic importance and used against a wide spectrum of bacterial ailments."-16 Diverse biological activities have been encountered in 8-Hydroxyquinoline and its derivatives are reported as compounds having the quinazoline ring ~ y s t e m . l ~In- ~ ~ well known antimicrobial agent~.l-~ In many cases the previous work, the synthesis and antimicrobial activities antimicrobial activity of 8-hydroxyquinoline derivatives of certain quinazolines containing pep tide^,^^ salicylic has been attributed to the chelating properties provided by the 8-hydroxyl group and the quinoline ring n i t r ~ g e n . ~ acid,39 sulfa drug moieties,*' and oxadiazolin-5-thione rnoieties4l have been described. From this point of view Some metal complexes of 8-hydroxyquinoline have been it was very interesting to synthesize some 8-quinolyl-astudied due to their established biological activities.'-'' mercaptoacetates (V), 8-quinolinoxythioacetate derivThe most commonly known bactericidal 8-hydroxyatives (VI) and 8-quinolyl-a-sulfonylacetates (VII) with quinoiine derivatives were obtained through ring substitution, for example 5,7-dichloro-8-hydroxyquinoline the aim of investigating their antimicrobial potency with (Haloquinol INN), 5-chloro-8-hydroxy-7-iodoquinoline special reference to the starting 8-hydroxyquinoline. The (Clioquinol) and 8-hydroxy-7-iodo-6-quinolinesulfonic effect of the side chain variation, as ester and ether, upon the antimicrobial action will also be discussed. acid (Chiniofon).' Also it was very interesting to synthesize a new series Furthermore some sulfur-containing compounds are of quinazoline derivatives containing sulfides and sulfones with the aim that the incorporation of a quinazoline moiety with aryl and/or heterocyclic mercaptans may * To whom correspondence should be addressed. play a significant role in improving the antimicrobial t Accepted and orally presented at AAPS, Nov. 4-9, 1990, Las activity. Vegas, USA. 329 25-2 INTRODUCTION
M . F. El-Zohry et al.
330 EXPERIMENTAL The time required for completion of the reaction was monitored by thin layer chromatography (TLC). Melting points were determined in open glass capillaries and are uncorrected. IR-spectra were recorded on a Pye-Unicam SP 200G spectrophotometer. 'H-NMR spectra were measured in dimethyl sulfoxide-d, or trifluoroacetic acid using TMS as internal standard on EM 360 90 MHz NMR spectrophotometer. Microanalyses were determined on a Perkin-Elmer 240 C microanalyser. 8-Quinolyl-a-chloroacetate (II)" In a two-necked round bottomed flask (250 ml) fitted with a reflux condenser and a 50ml dropping funnel, 5.8 g (0.04 mole) 8-hydroxyquinoline was dissolved in 100 ml dry pyridine. To the stirred solution there was added dropwise 2.0 ml (2.5 g, 0-022 mole) of freshly distilled chloroacetyl chloride. The reaction mixture was then stirred for 2 h at room temperature and then filtered. The golden yellow precipitate was crystallized from petroleum ether (60-8OoC), m.p. 21 8-220°C.
8-Quinolinoxyacetyl chloride (IV)4394-1 A solution of 2.46 g (0.044 mole) of potassium hydroxide in 100ml absolute ethanol was prepared. To this
solution, 3.1 g (0.022 mole) of 8-hydroxyquinoline was added, then 2.5 g (0026 mole) of chloroacetic acid was added portionwise. The solution was refluxed with stirring for 20 h. After cooling to room temperature the reaction mixture was acidified by 5 ml of conc. HCl, and filtered to remove the precipitated KCI. The ethanol was removed under reduced pressure to afford the corresponding acid which was converted to the acid chloride by treatment with 2.5 ml of thionyl chloride in 50 ml dry benzene and subsequent reflux for 1 h. The solvent and excess thionyl chloride were removed by distillation under reduced pressure. The residual acid chloride was crystallized from petroleum ether (6O-8O0C), then was used for synthesis of the thioacetate derivatives VIa-e.
Reaction of 8-chloroacetoxyquinolineand/or 8quinoloxyacetyl chloride with aryl(heterocyc1ic)mercaptans A 0.01 mole amount of 8-chloroacetoxyquinoline (11) and/or 8-quinoloxyacetyl chloride (111) was dissolved in 25 ml dry benzene. To this solution 0.01 mole of the aryl(heterocyc1ic)mercaptan was added portionwise and the mixture was refluxed for 8 h. Benzene was removed under reduced pressure and the product was crystallized from the appropriate solvent (Tables 1 and 2).
TABLE 1 Physical Properties, Yields and Elemental Analyses of the 8-quinolyl-a-mercapto(sulfonyl)acetateDerivatives (V, VII) Compound
Yield (YO)
X
m.p.
("c)
Microanalyses-Calcdl found (YO)
Molecular formula C
H
N
s
CI
~
Va
73
220-2"
Vb
72
245"
vc
65
140-2'
Vd
72
210-12c
Ve
63
1 70b
VIIa
70
80-2"
VIIb
73
624"
VIIC
73
120-2"
VIId
75
60-3"
69-90 69-50 62-02 62.30 61.36 61.20 64.67 . 64.50
C18H1304N3S
(366) 65
VIIe
115-17d
C14H1104N3S
(3 17) Ethanol/water.
' Ethanol.
l1
Methanol. Methanollwater.
58.94 58.50 63.34 63.30 56.50 5630 56.25 56.70 59.01 58.50 52.95 5220
4.85 4.80 3.64 3.50 3.40 3.40 3.59 3.20 3.85 3.70 4.30 4.18 3.30 3.20 3.10 2.50 3.24 3.10 3.40 3.10
4.53 4.30 425 4.20 7.95 7.80 12.59 12.40 14'73 14.40 4.12 3.90 3.87 3.40 7.29 7.90 11.47 11.20 13.20 12.99
10.35 10.50 9.72 10.00 18.18 18.50 9.58 9.30 11.22 11.30 9.38 8.60 8.80 8.30 16.60 16.40 8.70 8.21 10'09 9.70
-
-
10.6 10.6 -
-
-
-
-
Properties of quinoline and quinazoline derivatives
331
TABLE 2 Physical Properties, Yields and Elemental Analysis of 8-quinolinoxythioacetate Derivatives (VIa-e)
Compound
X
Yield (YO)
m.p.
(“0
Mieroanalyses-Calcd/found (YO)
Molecular formula
VIa
S
83
2 15-7“
VIb
S
73
230-2”
VIC
S
65
260-2“
VIQ
S
72
190-2“
C18H1202N3S
VIe
S
63
160-lb
C14H110ZN3S
~,,Hl,OZNS (309) Cl,H12C10zNS (329) Cl8H12O2NZS2 (352) (334) (285)
Oxidation of 2’-Aryl(heterocyclic)mercapto-8acetoxyquinoline (Va-e) (general procedure)
2’-Aryl(heterocyclic)mercapto-8-acetoxyquinoline (0-01 mole) was dissolved in glacial acetic acid, then the calculated volume of hydrogen peroxide (30 YO)was added dropwise. The reaction mixture was left to stand for 3 days at room temperature, then the combined solvents were removed and the products VIIa-e were crystallized from the appropriate solvents (Table 1). Preparation of 3-(2’-hydroxyethyl)-2-methyl-3,4dihydraquinazolin-4-one (IX) and 3-(2’-chloroethyl)-2methyl-3,4-dihydroquinazolin-4-one(X) These compounds were synthesized according to the reported procedure^.^^ Synthesis of 3-(aryl(heterocyclic)mercaptoethyl)-2methyl-3,4dihydroquinazolin-4-ones (XIa-h) A solution of 0.025 mole of the aryl mercaptan and/or heterocyclic mercaptan was added to 0.025 mole of X in 50 ml ethanol containing 0.025 mole sodium hydroxide. The reaction mixture was refluxed on a water bath for 4 h, then cooled to room temperature while the desired product precipitated. The product was filtered off, washed with cold water, dried and crystallized from the appropriate solvent. Physical properties of compounds XIa-h are depicted in Tables 3 and 4. Synthesis of 3-(aryl(heterocyclic)sulfonyIethyl)-2-methyl3,4-dihydroquinazolin-4-ones (XIIa-h) A solution of 0001 mole of XIa-h was dissolved in 20 ml of AcOH, to this solution there was added 10ml of H,O,. The reaction mixture was warmed on a water bath at 70°C for 3 h, then cooled to room temperature,
C
H
N
S
69.90 69.61 62.02 62.50 61.36 61.10 64.67 64.30 58.94 58.60
4.85 4.70 3.64 3.40 3.40 3.21 3.59 3.30 3.85 3.60
4.53 4.41 4,25 4.25 7.95 7.70 12.57 12.30 14.73 1400
10.35 1020 9.72 9.50 18.18 18.20 9.58 9.20 11.22 11.10
Cl
whereby the desired sulfones XIIa-h were precipitated, filtered off, dried and crystallized from the appropriate solvent. Physical properties of XIIa-h are shown in Tables 3 and 4. RESULTS AND DISCUSSION The reaction of 8-hydroxyquinoline (I) with chloroacetyl chloride in pyridine proceeds very smoothly at room temperature giving 8-quinolyl-a-chloroacetate (11) in good yields. The reaction of compound I1 with the appropriate aryl and/or heterocyclic mercaptans afforded the 8-quinolylesters (Va-e) (Scheme 1). Physical constants, yields and elemental analyses of compounds Va-e are presented in Table 1. 8-Quinolinoxythioacetates (VIa-e) were also obtained by the interaction of the same series of aryl and/or heterocyclic mercaptans and 8-quinolinoxyacetyl chloride (IV) under the same conditions in boiling benzene. The latter intermediate (IV) was readily accessible through reaction of 8-hydroxyquinoline with chloroacetic acid followed by treatment of the 8-quinolinoxyacetic acid (111) produced with thionyl chloride in dry benzene. The physical constants, yields and elemental analyses of the 8-quinolinoxythioacetate derivatives (VIa-e) are summarized in Table 2. The 8-quinolyl-a-mercaptoacetate derivatives Va-e were subjected to oxidation to explore the effect of this type of sulfur linkage, in the side chain, on the antibacterial activity. Sulfones (VII), were obtained by the oxidation of the corresponding mercapto derivatives (Va-e) with hydrogen peroxide in glacial acetic acid at room temperature. The yields, physical constants and elemental analysis of compounds VIIa-e are shown in Table 1. The IR-spectra of the 8-quinolylacetate derivatives (Va-e) show a characteristic strong absorption band at
M . F. El-Zohry et al.
332
TABLE 3 Physical Properties of 3-(2’-aryl(heterocyclic)mercaptoethyl)-2-methyl-3,4-dihydroquinazolin-4-one (XIa-h) and 3-(2-aryl(heterocyclic)sulfonylethyl)-2-methyl-3,4-dihydroquinazolin-4-one(XIIa-h) Compound
Solvent of crystallization
m.p.
Yield
(“C)
(%I
Molecular formula
Analysis calcd (found) (YO) C
H
N
XIa
Ethanol
18&2
82
C,,H,,ON,S
68.91 (68.87)
5.40 (5.36)
9.45 (9.72)
XIb
Ethanol
24&2
87
C,,H,,ON,S
69.67 (69.71)
5-80 (5.71)
9.03 (9.10)
XIC
Ethanolwater (1 : 1)
200-2
81
C,,H,,ON,SCl
61.81 (61.85)
4.54 (4.51)
8.48 (8.79)
Xld
Ethanolwater (1 : 1)
300-2
79
C,,H,,ON,S
69.67 (69.70)
5.80 (5.71)
9.03 (9.32)
XIe
Ethanol
300-2
72
C,,H,,ON,S
72.83 (72.61)
5.20 (5.19)
8.09 (8.00)
XIf
Ethanolwater (1 : 1)
28&2
86
C,,H,,ON,S
58-74 (58.96)
4.89 19-59 (4.82) (19.56)
Xk
Ethanol
11&12
76
C,,H,,ON,S,
61.18 (61.49)
424 (418)
11.89 (12.18)
XIh
Methanol
85-7
69
C,,H,,ON,S
64.28 (64.22)
4.76 (468)
16.60 (16.56)
Xlla
Ethanol
190-2
87
C,,H,,O,N,S
62.19 487 (62.26) (4.66)
8.53 (842)
XIIb
Ethanolwater (1 : 1)
11@1-2
85
C,,H,,O,N,S
63.15 (63.46)
526 (5.20)
(8-12)
XIIC
Ethanol
160-2
81
C,,H,,O,N,SCI
56.35 (56.31)
4.14 (4.31)
7-73 (7-65)
XIId
Waterethanol (2: 1)
245
81
C,,H,,O,N,S
63.15 (63.31)
5.26 (5.20)
(8.12)
XIIe
Methanol
300
67
C,,H,,O,N,S
66.66 (66.72)
4.76 (459)
7-40 (7-32)
XIIg
Methanol
18&2
81
C,,H,,O,N,S,
5610 (56.20)
3.89 (3.75)
10.90 (10.95)
XIIh
Methanol
110-12
78
c,,H,,o,N,s
58.69 (58.57)
4-34 (469)
15.21 (15.30)
8.18
8.18
IR (KBr), cm-l
S
10.81 3040 (CH arom), 2920 (10.71) (CH aliph), 1680 (C=O), 1600 (C=N inside the ring), 700 (C-S) 10.32 3045 (CH arom), 2927 (10.27) (CH aliph), 1690 (C=O), 1610 (C=N), 710 (C-S) 9-69 3025 (CH arom), 2930 (9.58) (CH aliph), 1700 (C=O), 1605 (C=N), 800 (C-Cl), 695 (C-S) 10.32 3010 (CH arom), 2900 (1047) (CH aliph), 1690 (C=O), 1600 (C=N), 700 (C-S) 9.24 3020 (CH arom), 2950 (9.57) (CH aliph), 1705 (C=O), 1650 (C=N), 695 (C-S) 11.18 3400 (NH), 3010 (CH arom), (I 1.10) 2970 (CH aliph), 1710 (CEO), 1690 (C=N), 690 (C-S) 1813 3015 (CH arom), 2980 (18.06) (CH aliph), 1700 (C=O), 1680 (C=N), 700 (C-S) 9.52 3445 (NH), 3050 (CH arom), (949) 3000 (CH aliph), 1710 (C=O), 1600 (C=N), 700 (C-S) 975 3040 (CH arom), 2930 (CH (9-91) aliph), 1700 (C=O), 1620 (C=N), 1400 (SO,), 700 (C-S) 9.35 3045 (CH arom), 2930 (CH (9.31) aliph), 1700 (C=O), 1675 (C=N), 1420 (SO,), 710 (C-S) 8.83 3020 (CH arom), 2950 (CH (8.62) aliph), 1690 (C=O), 1620 (C=N), 1420 (SO,), 800 (C-Cl), 700 (C-S) 9.35 3040 (CH arom), 3000 (CH (9.61) aliph), 1700 (C=O), 1650 (C=N), 1410 (SO,), 700 (C-S) 8.46 3055 (CH arom), 2900 (CH (8.61) aliph), 1710 (C=O), 1640 (C=N), 1420 (SO,), 700 (C-S) 16.62 3050 (CH arom), 2970 (16.51) (CH aliph), 1705 (CEO), 1685 (C=N), 1420 (SO,), 700 (C-S) 8.69 3455 (NH), 3050 (CH (8.89) arom), 2990 (CH aliph), 1700 (C=O), 1630 (C=N), 1380 (SO,), 695 (C-S)
Properties of quinoline and quinazoline derivatives
333 TABLE 4
'H-NMRData of 3-(2'-aryl(heterocyclic)meracptoethyl)-2-methyl-3,4-dihydroquinqzolin-4-one (XIb, e) and 3-(2'-aryl(heterocyclic)sulfonylethyl)-2-methyl-3,4-dihydroquinazolin-4-one(XIIa, b, c, e) 'H-NMR (solvent), G(TMS) pprn
Compound
(DMSO.d,) 25 (3H,S), 3.0 (3H,S), 3.8-4.0 (2H,t), 4.3-45(2H,t), 7.5-7.71(4H,m), 7.9-8 (2H,d), 8.1-8.3(2H,d) (CF,COOH)3.2 (3H,S), 4.M.1(2H,t), 4.5-4.7(2H,t), 7.5-7.8(4H, m), 7.95 (2H,d), 8.3-8.4(2H,d) (CDCl,/CF,COOH) 2.4(3H,S), 3.9(2H,,)t 4.3 (2H,t), 7.3-8.0(8H,m), 8.3(2H,d) (CDCl,/DMSO.d,) 2.6 (3H,S), 3.6 (2H,t), 4.4(2H,t), 7.2-7.6 (5H,m), 7.8 (2H,d), 79-8.1 (2H,d) m), 7.9-8.0(2H,d), 8.1-8.3(2H,d) (DMSO.d,) 2.6 (3H,S), 3.0(3H,S), 3.84.0(2H,t), 4.345 (2H,t), 75-7.7 (4H, (DMSO.d,)/CF,COOH) 3-1(3H,S), 4-3(2H,t), 4.5-4.7(2H,t), 7.6-7.8 (4H, m), 7-9(2H,d), 8-3-8.4(2H,d) (DMSO.d,/CF,COOH) 26 (3H,S), 3.9(2H, t), 4.3 (2H,t ) , 76-8.0 (8H,m), 8.3 (2H,d)
XIb XIC XIe XIIa XIIb XIIC XIIe
~
~ ~ r ~ ~ ~ e c l
ArSH
H202/AcoH
25" C
OCOCH,CI
OCOCH,SAr
II
OCOH2S0,Ar
Vlla-e
Va-e
OH I
\(1)c1CH2coo~
NaOH/ethanol (2) dil. HCI N
ArSH
eb::::
' OCH,COOH
I
OCH,COCI
111
OCH,COSAr
IV
Vla-e
H
H
Scheme 1
1 7 3 ~ ~cm-l 4 0 corresponding to the stretching vibrations of C=O group in the ester function. It was observed that substitution at the a-position of the side chain does not considerably influence the frequency of this carbonyl vibration. Also when the a-positioned sulfur atom was oxidized to the corresponding sulfone function to afford compounds VIIa-e, there was no observable change in the frequency of the carbonyl ester in comparison with the parent compounds Va-e. The a-sulfonyl derivatives are characterized furthermore by the appearance of a new band at 1410 cm-' corresponding with the -SO, group. In the 8-quinolinoxythioacetate derivatives (VIa-e) the frequency of the carbonyl group is generally lowered to 1700-1690 cm-I due to the presence of the sulfur atom in the ester moiety instead of oxygen. 'H-NMR spectra were taken in trifluoroacetic acid for some of the synthesized compounds. The general feature
-
for all derivatives is the presence of the singlet, integrated for 2H, in the range between 63.9 and 35ppm. The aromatic protons appear as a complex system in the range between 67.8 and 9.3 ppm. Some signals could be identified such as that at 69.4 ppm (1H) with characteristic ortho coupling (- 5 Hz), this signal was assigned to H-2 of the quinoline ring. Its downfield shift with respect to the other protons is due to the ring nitrogen. The triplet at 69.2 ppm, integrated for 2H, is assigned to H-3 and H-6 of the quinoline nucleus. The splitting pattern of this signal is attributed to the two ortho protons H-2/H-4 and/or H-5/H-7. The other aromatic protons of the side chain substituent appear in the range between 7.2 and 8-0 ppm. Going to the synthesis of quinazolin-4-one derivatives, our precursor 2-methyl-(3,l)-benzoxazin-4-one(VIII) was allowed to react with ethanolamine to afford the
M . F. El-Zohry et al.
334
R
0
X
IX
Vlll
9
9 AcOH ~ ~
- &4rH2CHzSOzAr 0 ,
NaOH/ ethanol
CH3
XI1 a-h
XI a-h
H Scheme 2
corresponding alcohol (IX). The reaction of IX with thionyl chloride gave the corresponding chloro derivatives X. The reaction of X with aryl mercaptans and/or heterocyclic mercaptans in sodium hydroxide yielded 3-(2'-arylmercaptoethyl)-2-methyl-4-(3H)quinazolin-4-ones and/or 3-(2'-heterocyclic mercaptoethy1)-2methyl-4(3H)quinazolin-4-ones (XIa-h). Oxidation of compounds XI using hydrogen peroxide in acetic acid, gave the corresponding sulfones XIIa-h (Scheme 2). The structure assignment of the prepared compounds XIa-h and XIIa-h was elucidated by their elemental and spectral analyses (cf. Tables 3 and 4). Antimicrobial Activity The antibacterial activity of the newly synthesized compounds was tested against the following organisms : Gram-positive-Staphylococcus aureus ATCC 25923, NCTC 6571, DSM 1104; Gram-negative-Escherichia coli ATCC 25823, NCTC 1048, DSM 10. Agar cup diffusion techniques were used and tetracycline HCl was used as a standard reference. The synthesized compounds Va-e, VIa-e and VIIIa-e were tested for their antimicrobial activity using agar cup diffusion techniques.*' Their minimum inhibitory concentration (MIC) was calculated @g 1-l) against Staphylococcus aureus and Escherichia coli. This method
depends on the diffusion of the drug tested from cylinders or from wells placed on the surface of seeded agar. As the plate is incubated, the drug diffuses into the medium giving zones of progressively lower concentration, The test organism can grow up to the zone on minimum inhibitory concentration but not inside it. For determination of MIC of the tested compounds five different concentrations of each compound (5, 2.5, 1.25,0.625,031 pg) in 1 ml DMSO were prepared under sterile conditions and transferred to the appropriate wells in the preinoculated agar plates. Five equivalent concentrations of 8-hydroxyquinoline were also prepared and tested against the same microorganisms. After incubation of the petri dishes at 37°C for 48 h, the diameter of inhibition zones for each concentration of the considered compounds were measured. The MIC values were then calculated mathematically according to the linear regression equation : Y=a+bX where Y = square of the diameter of inhibition zone in mm;
X = log concentration in ,ug ml-'; a = constant value corresponding to the intercept;
b = slope of the linear regression line; a/b = log MIC.
Properties of quinoline and quinazoline derivatives
TABLE 5 MIC (pg ml-l) Compound
Va Vb vc Vd Ve 111 I
VIa VIb VIC VId VIe Tetracycline
MIC" (correlation coeficient)
E. coli
S. aureus
10.7 (098) 3.1 (0966) 3.8 (0.989) 1.4 (0930) 1.4 (0.98) 4.6 (0.673) 9.6 (0.959) 4.4 (0.978) 3.1 (0.945) Inactive 3.8 (0.989) 3.9 (0.991) 3.6 (0.99)
18.2 (0.991) 10.5 (0.986) 2.7 (0945) 1.9 (0.997) 1.9 (0.99) 4.1 (0.614) 4.0 (0,992) 2.1 (0.981) 2.8 (0.981) Inactive 4.3 (0.999) 3.4 (0,974) 4.0 (0.99)
Table 5 gives the calculated MIC values ,ug 1-' for the tested compounds with their corresponding correlation coefficients. From the analysis of the MIC data given in Table 5, it was observed that the thioacetate derivatives VIa-e exhibit higher antimicrobial activities than the corresponding a-mercaptoacetates (Va-e) and also higher than the starting 8-hydroxyquinoline (I) and its 8quinolineoxyacetic acid (111). Oxidation of the sulfur linkage in the side chain of mercaptoacetate derivatives Va-e to their corresponding TABLE 6 Molar Minimum Inhibitory Concentration (MIC pg ml-l) Compound
XIa XIb XIC XId XIe XIf XI&! XIh XIIa XIIb XIIc XIId XIIe XIIf XIIg XIIh Tetracycline
MIC (pg ml-')
E. coli
S. aureus
Inactive Inactive 050 ( r = 0.99) 060 ( r = 0.98) 0.30 (r = 0.99) Inactive Inactive Inactive Inactive 0 2 0 (r = 098) 0.40 ( r = 0.99) 0.30 ( r = 098) Inactive Inactive Inactive Inactive 0.35 ( r = 0.99)
Inactive Inactive Inactive Inactive Inactive Inactive Inactive Inactive Inactive Inactive 0.30 (0.99) 0.40 (0.98) Inactive Inactive Inactive Inactive 038 (0.99)
335
sulfones VIIa-e abolished the antimicrobial activity. Within the series of 8-quinolyl-a-mercaptoacetate (Va-e), it was found that the side chain bearing heterocyclic moiety as compounds Vd and Ve showed higher antimicrobial activity than those with an aryl substituent (Va, Vb and Vc). For the 8-quinolinoxythioacetate derivatives (VIa-e), most of the tested compounds showed generalized activity against the S. aureus and E. coli bacteria species tested but VIa and VIb showed higher activity against S. aureus than did VId and VIe. Within the series of quinazoline derivatives containing sulfide moiety, the compounds which showed the most potent inhibition of E. coli were the compounds having the chlorophenyl (XIc), benzyl (XId) and naphthy1 moiety (XIe). For the quinazoline derivatives containing the sulfone moiety, XIIb showed high activity against E. coli while XIIc and XIId showed a generalized activity against S. aureus and E. coli bacteria species tested relative to tetracycline. Table 6 shows the MIC (ug ml-') values for the tested compounds XIa-h and XIIa-h.
REFERENCES 1. Tadeusz, F. M. & John, D. F., Tetrahedron Lett., 29(18) (1988) 2137. 2. Khalil, Z. H., Yanni, A. S., Abdel-Hafez, A. A. & Khaiaf, A. A., J. Indian Chem. Soc., 64(1) (1987) 42. 3. Sharada, J., Ratna, Y. K. & Kanakalingeswara, R. M., Indian J. Pharm. Sci., 49(1) (1987) 17. 4. Abdel-Hadi, A. Z., Zayed, S., Herb, A. A. & Manhi, F. M., Pol. J . Pharmacol Pharm., 38(1) (1986) 99. 5. Swhunack, W., Mayen, K. & Haake, M., In Arzneistofe, Lehrbuch der Pharmazeutische Chemie, 2 Aufl. Vieweg Verlag, Braunschweig, 1984, p. 533. 6. Proffit, E. & Buchmann, G., Arzneimittel-Forsch., 10 (1960) 181. 7. Nishihara, H., J. Biol. Chem. Jpn, 40 (1953) 579. 8. Williams, D. R., Chem. Rev., 72 (1972) 203. 9. Ibrahim, S.A., Makhlouf, M. Th., Abdel-Hafez, A. A. & Moharram, A. M., J. Inorg. Biochem., 28 (1986) 57. 10. Ghoneim, K. M., Osman, A. N., Said, M. & El-Keroch, T. A., Egypt. J . Pharm. Sci., 28 (1987) 17. 11. Chaurosia, M. R., Sharma, S. K. & Kumar, R., Indian J . Pharm. Sci., (1979) 152. 12. Snyder, H. R., Jr & Benjamin, L., J. Med. Chem., 13 (1970) 164. 13. Shimidzu, N. & Uno, T., Chem. Pharm. Bull., 26 (1978) 127. 14. Clayson, D. B., Pringle, J. A. S.& Ranses, G. M., Biochem. Pharmacol., 16 (1967) 614. 15. Beerlev, W. N., Peters, W. & Mayer, K., Ann. Trop. Med. Parasitol., 62 (1960) 288. 16. Tarbini, G., Proc. 5th Inst. Congr. Chemother., 2 (1967) 909. 17. Armarego, W. L. F., Advan. Heterocyclic Chem., 1 (1963) 253. 18. Baker, B. R., Schaub, R. E., McEvoy, F. J. & Williams, H. H., J. Org. Chem., 17 (1952) 132. 19. Ablondi, F., Gordon, S., Morton, J. & Williams, J. H., J. Org. Chem., 17 (1952) 19.
M . F. El-Zohry et al. 20. Camrridge, A. B., Jansen, A. & Jarman, D. A., Nature, 1% (1962) 1217. 21. Amin, A. H., Mehta, D. R. & Samrth, S. S., Proc. 1st Intern. Pharmacol. Meeting, Stockholm, 7 (1961) 371. 22. Gujral, M. L., Sareen, K. N. & Kohli, R. P. J., Med. Res., 145 (1957) 207. 23. Bianci, C. & David, A. J., Pharm. Pharmacol., 12 (1960) 501. 24. Boltz, K. H., Dell, H. D., Lehwald, H., Lorenz, D. & Aubert, M. Schweer, Arzneimittel-Forsch, 13 (1962) 688. 25. Petersen, S., Herlinger, H., Tietze, E. & Siefken, W., Angew Chem., 74 (1962) 855. 26. Revina, A., Presse Med., 67 (1959) 891. 27. Destevens, G., Diuretics. Academic Press Inc., New York, 1963, p. 112. 28. Leskovszky, G., Erdely, I. & Tardos, L., Acta Physiol. Acad. Sci. Hung., 27 (1964) 81. 29. Deysson, G. & Truhaunt, R., Ann. Pharm. France, 23 (1965) 229. 30. Maucevic, G., Stotzer, H. & Wick, H., ArzneimittelForsch., 15 (1965) 613. 31. Hsyao, S., Havera, H. J., Strycker, W. G., Leipzig, T. J., Kulp, R. A. & Hartzier, H. E., J. Med. Chem., 8 (1965) 807. 32. Kozhennikov, Yu. V., IZV. Vyssh. Ucheb. Zaved., a i m . Tekhol., 14 (1971) 1959; Chem. Abst., 77 (1972) 19599 P.
33. Buzas, A. & Hoffman, C., Bull. SOC.Cheim. France, 26 (1959) 1889. 34. Somasekhara, S., Dighe, V. S., Mankad, P. R. & Mukherjee, F. A., Indian J. Chem., 2 (1964) 369. 35. Dighe, V. S., Somasekhara, S., Bagabant, G. & Mukherjee, S. L., Current Sci. (Indian), 33 (1964) 78. 36. Peck, R. M., Connel, A. P. 0. & Creech, H. J., J. Med. Chem., 9 (1966) 217. 37. Preton, R. K., Peck, R. M., Breuninger, E. R., Miller, A. J. & Creech, H. J., J. Med. Chem., 7 (1964) 471. 38. El-Khawaga, A. M., Abd-Alla, M. A. & Khalaf, A. A., Gazzetta Chimica Italian, 111 (1981) 44-2. 39. Abd-Alla, M. A., Yanni, A. S., Ahmed, S. H. & AbdelRaheam, M. H., Bull. Pharm. Sci., Assiut University, 7 (1984) 22436. 40. Yanni, A. S. 81 Abd-Alla, M. A., Bull. Fac. Sci., Assiut University, 16 (1987) 55-9. 41. Ahmed, A. N., Abd-Alla, M. A. & El-Zohry, M. F., J. Chem. Tech. Biotechnol., 43 (1988) 63-70. 42. Behera, B., Rath, P. C. & Rout, M. K., J. Indian Chem. Soc., 44 (1967) 119-22. 43. Nagel, O., Monatsh. Chem., 18 (1897) 32. 44. Rasshofer, Mueller, W. M. & Voegtle, F., Chem. Ber., 112 (1979) 2095-119. 45. Singh, P., J. Indian Chem. Soc., IV (1978) 801-5. 46. Collins, C. H., Microbiological Methods. Butterworths, London, 1964, p. 92.
