научная статья по теме SYNTHESIS AND EVALUATION OF IN VITRO ANTIMICROBIAL ACTIVITY OF NOVEL 2-[2-(AROYL)AROYLOXY]METHYL-1,3,4-OXADIAZOLES Химия

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EHOOPrAHH^ECKAa XHMH3, 2014, moM 40, № 3, c. 357-362

SYNTHESIS AND EVALUATION OF IN VITRO ANTIMICROBIAL ACTIVITY OF NOVEL 2-[2-(AROYL)AROYLOXY]METHYL-1,3,4-OXADIAZOLES

© 2014 V. Girish*, Noor Fatima Khanum**, H. D. Gurupadaswamy*, Shaukath Ara Khanum*, #

*Department of Chemistry, University of Mysore, Yuvaraja's College, Mysore, 570005India **Department of Food Science and Nutrition, Maharani's Science College, Mysore, 570006India Recevied July 22, 2013; in final form, October 21, 2013

Synthetic pathway of the ten novel 2-[2-(aroyl)aroyloxy]methyl-1,3,4-oxadiazoles as new potential antimicrobial agents is illustrated. Intramolecular cyclization of 2-(2-aroylaryloxy) aceto hydrazides to 2-[2-(aroyl)aroyloxy]methyl-1,3,4-oxadiazoles was achieved with triethyl orthoformate in good yields. The compounds were characterized by IR, 1H NMR, mass spectra and by means of CHN analysis. The target compounds were tested for their in vitro antimicrobial activity against representative strains by disc diffusion method and micro dilution methods. Several compounds showed antimicrobial activity comparable with or higher than the standard drugs.

Keywords: benzophenones, 1,3,4-oxadiazoles, antimicrobial activity, MIC

DOI: 10.7868/S0132342314030063

INTRODUCTION

The problem of increasing antimicrobial resistance among bacterial and fungal pathogens is of growing concern to physicians, microbiologists, research scientists and professionals of the pharmaceutical industry [1, 2]. Even though pharmacological industries have produced a number of new antibiotics in the last three decades, resistance to these drugs by microorganisms has increased [3]. In general, microorganisms have the genetic ability to transmit and acquire resistance to drugs, which are utilized as therapeutic agents

[4]. This is a cause for concern, because a number of patients have suppressed immunity, and due to new bacterial and fungal strains, which are multi-resistant

[5]. Consequently, new infections can occur resulting in high mortality [6, 7]. Therefore, action must be taken to counter this problem. For example, measures such as the controlled use of antibiotic, development of research to a better understanding of the genetic mechanisms of resistance and to continue studies to develop new drugs, either synthetic such as sulfonamides nitrofuranes, penicillins, cephalosporins, tetracycline's macrolides, and oxazolidinones [8, 9], or natural. The ultimate goal is to offer appropriate and efficient antimicrobial drugs to the patient.

The inhibitors of microorganism growth under standardized conditions may be utilized in demonstrating the therapeutic efficacy of drugs. Any subtle change in the drug molecule, which may not be de-

# Corresponding author (phone: 9901888755; e-mail: shaukathara@yahoo.co.in).

tected by chemical methods can be revealed by a change in the antimicrobial activity and hence microbiological assays are very useful for resolving doubts regarding possible changes in the potency of drugs and their preparation. The microbial assay is based upon the compulsion of inhibition of growth of microorganisms by marked concentration of the synthetic or natural compounds to be examined with that produced by the known concentration of a standard drug having a known activity [10].

Compounds containing benzophenone [11, 12] and 1,3,4-oxadiazole moieties [13, 14] find a unique place in medicinal chemistry. 1,3,4-Oxadiazole is associated with potent pharmacological activity due to the presence of toxophoric —N=C—O— linkage. Considerable evidences have been gathered to reveal the efficiency of 1,3,4-oxadiazole including antimicrobial activity [15]. The synthesis of oxadiazoles continues to attract interest, due to its interesting structural implications of the biological systems. In view of these observations and our continued interest in the synthesis of biologically active heterocyclic compounds [16], it was worthwhile to synthesize integrated 1,3,4-oxadia-zole moiety to a benzophenone framework.

RESULTS AND DISCUSSION

The reaction sequence for the title compounds is outlined in Scheme. Compounds (1a—j) to (3a—j) have been prepared as previously reported by our group [16—18]. Compounds (3a—j) with triethyl orthoformate underwent intramolecular cyclization,

to yield substituted 2-[2-aroylaroyloxymethyl]-1,3,4-oxadiazoles (4a—j). The antimicrobial activities of synthesized compounds were screened against eight bacteria and four fungi using in vitro disc diffusion method. The results revealed that most of the synthesized compounds exhibited antimicrobial activities against Staphylococcus aureus, St. aureus (MRSA), Enterobacter aerogenes, Micrococcus luteus, Klebsiella pneumonia, Salmonella typhimurium, S. paratyphi-B, Proteus vulgaris, Candida albicans, Botyritis cinerea, Malassesia pachydermatis, and C. krusei organisms. The results are summarized in Table 1 and 2. Compounds (4a), (4d), (4g), (4h), and (4j) showed good activity more than standard drug against S. aureus. Compound 4a with methyl and chloro groups at the para position in phenyl ring and the meta position in

benzoyl ring, respectively showed good activity against both Gram-positive and Gram-negative bacteria among all synthesized compounds compared with the standard. Among the compounds (4g—j) in which chloro group is substituted in the phenyl ring compounds (4g), (4h) and (4j) show good activity against S. aureus. Compound (4a) showed significant antifun-gal activity against B. cinerea and C. krusei. In contrast, compounds (4b) and (4i) with bromo and (4c) with methoxy groups exhibited lowest activity and this can be attributed to the bulkiness of bromo and meth-oxy groups which might render the molecule to penetrate through the cell wall. The MIC values of active compounds (4a), (4d—h) and (4j) against bacteria and fungi are given in Table 3 and 4 respectively.

R2

R2

R

1a-j

2a-j

O.

H2N-NH2H2O C2H5OH

O

R2

R2

3a-j

4a-j

a: R = CH3, R1 = R3 = H, R2 = Cl b: R = CH3, R1 = Br, R2 = R3 = H c: R = CH3, R1 = R2 = H, R3 = OCH3 d: R = CH3, R1 = R2 = R3 = H e: R = CH3, R1 = R2 = H, R3 = Cl f: R = R3 = CH3, R1 = R2 = H g: R = R2 = Cl, R1 = R3 = H h: R = Cl, R1 = R2 = R3 = H i: R = Cl, R1 = Br, R2 = R3 = H j: R = Cl, R1 = R2 = H, R3 = CH3 Scheme 1. Synthesis of 2[2-(aroyl)aroyloxy]methyl-1,3,4-oxadiazoles.

Significant MIC values were observed against Gram-positive and Gram-negative bacteria. Compounds (4a), (4e), (4g), (4h) and (4j) showed good activity against S. aureus. In comparison to compound

(4d), the presence of chloro group in the benzoyl ring in compounds (4a) and (4e) increased the potency against S. aureus by one fold. Interestingly the presence of chloro group in the phenyl ring in compounds

Table 1. In vitro antibacterial activity of compounds (4a—j)

Zone of inhibition in mm

Compounds Gram-positive bacteria Gram-negative bacteria

S. aureus S. aureus (MRSA) E. aerogenes M. luteus K. pneumonia S. typhimurium S. Paratyphi-B P. vulgaris

(4a) (4b) (4c) (4d) (4e) (41) (4g) (4h) (4i) (4j) Streptomycin 19 10 11 18 16 15 23 21 12 23 17 17 9 9 9 13 11 14 13 10 15 22 22 9 9 11 14 15 13 17 10 18 24 23 10 10 14 14 13 19 18 11 16 26 25 11 9 14 14 11 13 11 10 14 22 26 10 10 16 13 17 20 20 12 23 25 29 9 7 10 12 9 11 9 7 9 19 27 9 11 11 10 12 16 13 9 17 24

(4g), (4h) and (4j) increased the potency against S. aureus by two fold. In comparison to compound 4d in 4a the potency is increased by two fold against bacteria S. paratyphi-B, three fold by S. aureus (MRSA) and S. ty-phimurium, four fold by M. luteus and K pneumonia and fivefold by E. aerogenes. Besides, the potency of compound (4a) is increased by two fold against fungi B. cinerea, three fold by C. krusei and four fold by C. albicans compared to compound (4d). In general, compound (4a) showed better activity than standard drugs for most of the tested bacteria and fungi.

EXPERIMENTAL

Chemicals were purchased from Aldrich Chemical Co. TLC was performed on aluminum-backed silica plated with visualization by UV-light. Melting points were determined on a Thomas Hoover capillary melting point apparatus with a digital thermometer. IR spectra were recorded in Nujol on FT-IR Shimadzu 8300 spectrometer and XH NMR spectra were recorded on a Bruker 400 MHz spectrometer in CDCl3. Chemical shifts were recorded in parts per million downfield from tetramethylsilane. Mass spectra were obtained with a VG70-70H mass spectrometer and the elemental analysis (C, H, and N) was performed on Elementar Vario EL III elemental analyzer.

The synthesis of the hitherto unreported title compounds is as outlined in Scheme in 65—73.5% yield. Hydroxy benzophenones (1a—j) on reaction with ethyl chloroacetate affords ethyl (2-aroylaryloxy)acetates (2a—j) in excellent yield, which on treatment with hydrazine hydrate yields corresponding 2-(2-aroylary-loxy)acetohydrazides (3a—j) [16—18]. Intramolecular cyclization of (3a—j) with triethyl orthoformate result-

ed substituted 2-[2-aroylaroyloxymethyl]-1,3,4-oxa-diazoles (4a—j).

Synthesis of 2-[2-(3-chlorobenzoyl)-4-methylphe-noxy]methyl-1,3,4-oxadiazole (4a): A suspension of compound (3a) (0.52 g, 1.6 mmol) in triethyl ortho-formate (10 mL) was refluxed until (3a) disappeared. A solid was separated on cooling, which was filtered off, dried and recrystallized from ethanol to afford compound (4a). Compounds (4b—h) were synthesized analogously starting with derivatives (3b—h), respectively.

(4a): Yield 72%. M.p. 116-118°C; IR (Nujol): 1648 (C=N), 1665 cm-1 (C=O); 1H NMR (CDCl3): 8 2.3 (3 H, s, CH3), 4.55 (2 H, s, CH2), 6.85-7.7 (7 H,

Table 2. In vitro antifungal activity of compounds 4a—j

Compounds Zone of inhibition in mm

C. albicans B. cinerea M. pachydermatis C. krusei

(4a) 19 16 20 22

(4b) 9 11 10 12

(4c) 9 7 10 8

(4d) 11 10 12 14

(4e) 9 10 13 14

(41) 15 11 13 12

(4g) 11 9 12 10

(4h) 11 12 11 13

(4i) 10 9 10 7

(4j) 13 12 11 15

Keto-

conazole 22 10 26 16

Table 3. MIC (p.

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