Original Article DESIGN, SYNTHESIS AND MOLECULAR DOCKING STUDY OF HYBRID QUINOLINE-4-YL- OXADIAZOLES/OXATHIADIAZOLES AS POTENT ANTIFUNGAL AGENTS FIROZ A. KALAM KHAN, JAIPRAKASH N. SANGSHETTI* Dr Rafiq Zakaria Campus, Y. B. Chavan College of Pharmacy, Aurangabad 431001 (MS) India Email: jnsangshetti@rediffmail.com Received: 02 Jan 2015 Revised and Accepted: 26 Jan 2015 ABSTRACT Objective: The aim of the present work was to design and synthesize hybrid quinoline-4-yl-oxadiazoles/oxathiadiazole derivatives and evaluate them for in vitro antifungal activity against human disease causing pathogens. Methods: The compounds 5(a-d), 6(a-d) and 7(a-d) were efficiently synthesized in good yields. The synthesized compounds were characterized using 1 H NMR, 13 C NMR and Mass spectra. The synthesized compounds were screened for in vitro antifungal activity and minimum inhibitory concentration (MIC) values were determined using standard agar method. Molecular docking study was performed against fungal enzyme P450 cytochrome lanosterol 14α-demethylase using V Life MDS 4.3 software. Results: The synthesized compounds had shown good to moderate in vitro antifungal activity. The compound 6a (MIC range = 15-25 µg/ml) from 1,2,3,5-oxathiadiazole-2-oxide series showed most potent activity amongst the synthesized compounds when compared with standard clotrimazole (MIC range = 12.5-25 µg/ml). The molecular docking study of synthesized compounds showed good binding interactions against active site of fungal enzyme P450 cytochrome lanosterol 14α-demethylase. Conclusion: The results of in vitro antifungal activity and molecular docking study revealed that the synthesized compounds have potential antifungal activity and can be further optimized and developed as a lead compound. Keywords: Quinoline, Oxadiazole, Oxathiadiazole, Antifungal activity, Molecular docking study, P450 cytochrome lanosterol 14α-demethylase. INTRODUCTION The resolute appearances of fungal infections followed by the expansion of several resistant fungal strains against clinically used antifungal arsenal have urged medicinal communities to look for new incorporations into the current armamentarium. Severe chances of fungal infections among immunosuppressive individuals due to the HIV infection, cancer treatments and organ transplantations [1-3] actuated additional urgency to generate new antifungal agents. Availability of the few classes of antifungal drugs restricts the choice of implementing doses to the patients, and a long term administration of these drugs is progressively associating with multi-drug resistant emergence [4]. Fluconazole, clotrimazole, ketoconazole, itraconazole, posaconazole and some other azole class of drugs are currently used as antifungal management [5]. However, their treatment failures were witnessed by the medical communities [6]. Therefore, development of new chemical scaffolds with novel structural features will be the remarkable breakthroughs. Fig. 1: Design of hybrid quinoline-4-yl- oxadiazoles/oxathiadiazoles having similar structural configuration as that of clotrimazole Quinoline is versatile nucleus and reported for wide range of biological activities. Quinoline derivatives have been also reported for antifungal activity [7-10]. Other heterocycles like oxadiazole [11, 12] and oxathiadiazole [13] have been also explored for antifungal activity. Based on these reports, we have coupled the quinoline nucleus with oxadiazole or oxathiadiazole rings to design novel hybrid quinoline-4-yl-oxadiazoles/oxathiadiazole derivatives. The novel compounds were designed in a way that the compounds should have similar structural configuration with that of clotrimazole (fig. 1). Based on above facts and in continuation of our research for identification of bioactive agents [14, 15] in the present study, we have designed and synthesized hybrid quinoline-4-yl- oxadiazoles/oxathiadiazole derivatives. The novel synthesized compounds were evaluated for in vitro antifungal activity. We have also performed the molecular docking study against fungal enzyme P450 cytochrome lanosterol 14α-demethylase. MATERIALS AND METHODS Chemicals used were purchased from commercial sources and used without further purification. The melting points were determined in open capillary tubes and are uncorrected. The homogeneity of the compounds was monitored by ascending thin layer chromatography (TLC) on silica gel-G (Merck) coated aluminum plates, visualized by iodine vapor. 1 H NMR and 13 C NMR spectra were recorded on a 400 MHz Varian-Gemini spectrometer and chemical shift reported in parts per million (ppm), using tetramethylsilane (TMS) as internal standard. Mass spectra were taken with Micromass-QUATTRO-II of WATER mass spectrometer. Synthesis of N'-hydroxy-2-phenyl-2-(quinolin-4-yl) acetimida - mides (4) With the view of objectives, we have started synthesis with 4- hydroxyl quinoline (1) as a starting material, which is available commercially. This 4-hydroxyl quinoline has been methylated using dimethyl sulphate to get 4-methoxy quinoline (2). This 4-methoxy quinoline compound on treatment with substituted International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 7, Issue 4, 2015 Innovare Academic Sciences