Elsevier

Bioorganic & Medicinal Chemistry

Volume 14, Issue 24, 15 December 2006, Pages 8271-8279
Bioorganic & Medicinal Chemistry

Green route for the heterocyclization of 2-mercaptobenzimidazole into β-lactum segment derivatives containing –CONH– bridge with benzimidazole: Screening in vitro antimicrobial activity with various microorganisms

https://doi.org/10.1016/j.bmc.2006.09.017Get rights and content

Abstract

The efficient and rapid synthesis of novel azetidin-2-ones 4aj has been established. Thus, both microwave and conventional condensation 2-{(1H-benzimidazol)-ylthio}-N′-2-(substituted phenyl) hydrazide with chloroacetylchloride were carried out in DMF-benzene solvent in the presence of Et3N catalyst. The microwave synthesis route afforded better yield with short time. The novel heterocycles were characterized by elemental analysis and spectral features. Some of the produced compounds were screened for their antimicrobial activity.

Introduction

2-Mercaptobenzimidazole derivatives are known to possess varied biological activities.1 2-Azetidinone derivatives have been reported to possess anti-inflammatory,2 anticonvulsant,3 fungicidal,4 antibiotic,5 anticancer,6 antielastase,7 antiviral,8 antimicrobial,9 antitumor,10 anti-HCMV,11 antibacterial12 activities and pharmalogical interest.13 The incorporation of a 2-oxoazetidine moiety in to 2-mercaptobenzimidazole scaffold enhances its activity.

In the last few years, microwave-induced organic reaction enhancement (MORE) has gained popularity as a non-conventional technique for rapid organic synthesis14 and many researchers have described accelerated organic reactions, with a large number of papers that have appeared proving the synthesis utility of MORE chemistry in routine organic synthesis.15, 16 It can be termed as ‘e-chemistry’ because it is easy, effective, economical, and eco-friendly, and is believed to be a step toward achieving green chemistry objectives. Within the framework of ‘Green Chemistry’ we have now developed an environmentally benign and novel approach for the synthesis of azetidine-2-ones. In view of the above, and in continuation to our earlier work on the application of MORE17, 18, 19 chemistry to organic synthesis and the biological importance of 2-azetidinones, we now report a simple, novel and environmentally benign approach using facile, microwave synthesis of 2-azetidinones 4aj from precursors 3aj and ClCH2COCl using triethylamine (TEA) as a catalyst (Fig. 1).

Section snippets

Results and discussion

Conventional methodology sometimes has lower yields than microwave protocols. Microwave irradiation facilitates the polarization of the molecule under irradiation causing rapid reaction to occur. A comparative study in terms of yield and reaction period is shown in Table 1. The MS spectral fragmentation pattern is presented (Scheme 2) as an additional evidence for the proposed structure 4a. The synthetic route of abovementioned compounds is shown in Scheme 1) . All the compounds synthesised

General

Regents, instrumentation and measurements: all reagents, 2-mercaptobenzimidazole, solvents and catalyst were of analytical grade and used directly. All the melting points were determined in PMP–DM scientific melting point apparatus and are uncorrected. The completion of reaction was monitored by thin-layer chromatography (TLC) using silica gel-G coated Al-plates (0.5 mm thickness, Merck) and spots were visualized by exposing the dry plates to iodine vapour. The product was purified by silica gel

1′-[(Benzimidazol-2-yl)thioacetamidyl]-3′-chloro-4′- (3,4,5-trimethoxyphenyl-azetidin-2′-one) (4b)

Mp 250 °C; Anal. Calcd for C21H21N4O5S: C, 57.16; H, 4.05; N, 15.27. Found: C, 57.14; H, 4.08; N, 15.25%; IR (KBr): υ (cm−1) 3335, 1335 (–NH–), 1660 (>Cdouble bondO, amidyl), 1720 (>Cdouble bondO, cyclic), 2825 (Ar–OCH3), 779 (C–Cl); 1H NMR (CDCl3-DMSO-d6): δ (ppm) 8.50 (s, 1H, –CONH–), 6.98–7.93 (m, 8H, Ar–H), 3.18 (d, 1H, >CH–Ar), 4.46 (s, 2H, S–CH2–), 4.1 (s, 1H, >CH–Cl), 8.4 (s, 1H, –NH–benzimidazole), 3.91(s, 3H, –OCH3); 13C NMR (CDCl3-DMSO-d6): δ (ppm) 127.1 (C1), 129.1 (C2, C6),126.4 (C3, C5), 153 (C4), 52.3 (>

Antibacterial activity (the zone of inhibition)

The antimicrobial susceptibility testing (AST) was accomplished by the Kirby Bauer method of disc diffusion method. The sample solution was prepared by dissolving 10 μg of each of the compound in 1.0 mL of Dimethylformamide (DMF). The sterilized Whatman filter paper (No. 1) discs of approximately 6 mm were dipped in sample solution and dried in oven. These discs were placed on the medium previously seeded with the organisms in petri dishes at suitable distances. The petri dishes were stored in an

Antifungal activity (the minimum inhibitory concentration)

Study design. Microdilution is used according to a standard protocol described by the NCCLS.26, 27 Three stains were tested each of the following species: Candida albicans (ATCC-64550), Candida krusei (ATCC-14243) and Aspergillus niger.

Medium. RPMI 1640 broth with l-glutamine without sodium bicarbonate and 0.165 μ MOPS buffer (34.54 g/L) was used. The medium was adjusted to pH 7.0 at 25 °C. Sterility of each bottle was performed before it was used.

Antifungal agents. Terbinafine was provided by the

Conclusion

In conclusion, this new method for the synthesis of 2-azetidinones using catalytic amount of Et3N in DMF under microwave irradiation offers significant improvements over existing procedures an thus, helps facile entry into a variety of 2-azetidinones of potentially high synthetic utility. Also, this simple and reproducible technique affords various 2-azetidinones with short reaction times, excellent yields and without formation of undesirable by-products.

A series of 2-azetidinone (β-lactam)

Acknowledgment

One of the authors (Krunal Desai) is thankful to the Head of the Chemistry and Bioscience Department of Veer Narmad South Gujarat University, Surat. We gratefully acknowledge the Gujarat Council on Science and Technology, Gandhinagar, for financial assistance (Grant no. GUJCOST/200389/MRP/2003-04/10689), and the Central Drug Research Institute at Lucknow for spectral analysis.

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