Synthesis and Biological Evaluation of Thiazole, Oxadiazole and Indole Derivatives

Abstract

This dissertation has been divided into four chapters and each chapter has its own numbering of compounds and references. General introduction related to the importance of natural products and natural product based drugs, drug designing and value of lead molecules in drug designing. This research work describes synthesis and bioactivities of different class of heterocycles such as thiazole, oxadiazole and indole analogs in search of important therapeutic agents. During this research study, a variety of thiazole, oxadiazole and indole analogs were synthesized and screened for enzyme inhibition studies (thymidine phosphorylase, α-glucosidase, urease and β-glucuronidase activities). The results obtained from this study are encouraging which are discussed separately in the forthcoming chapters 1, 2 and 3. In the first chapter, thiazole analogs are described. In the thiazole series, sixteen analogs (1-16) were synthesized and evaluated for thymidine phosphorylase inhibitory potential. Out of sixteen analogs, nine analogs such as analogs 1, 2, 3, 5, 6, 8, 10, 13 and 15 showed good phosphorylase inhibitory potentials when compared with the standard 7-Deazaxanthine. The remaining seven analogs showed moderate to good activity. In 2nd chapter, oxadiazole analogs are described. Sixteen analogs (1-16) of oxadiazole were synthesized and evaluated for thymidine phosphorylase activity. Out of sixteen analogs, fourteen analogs such as analogs 1-7 and 9-15 showed excellent thymidine phosphorylase inhibitory potentials which is many folds better than the standard 7-Deazaxanthine. Analog 16 showed good inhibitory potential while analog 8 remain inactive among the series. In chapter third, three series of indole are described. In first series, We have synthesized thirty-two (32) bis-indolylmethane analogs (1-32) with varying degree of β-glucuronidase inhibition potential ranging in between 0.10 ± 0.01 to 48.50 ± 1.10 μM when compared with the standard drug D-saccharic acid 1,4-lactone (IC50 value 48.30 ± 1.20 μM). All of thirty-two analogs 1-32, showed outstanding β-glucuronidase inhibitory potentials. In second series, eighteen derivatives (1-18) of bis-indolylmethane thiosemicarbazide were synthesized and evaluated for their urease inhibitory potential. These derivatives displayed varying degree of inhibition in the range of 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having an IC50 value 21.25 ± 0.90 μM. All derivatives showed outstanding urease inhibitory potentials which are many folds better than the standard thiourea. In third series, twenty one analogs of tris-indole hybrid scaffold with oxadiazole ring (1-21) were synthesized and evaluated for α-glucosidase inhibitory potential. All compounds displayed superior α-glucosidase inhibitory activities having IC50 value in the range of 2.00 ± 0.01-292.40 ± 3.16 μM as compared to standard acarbose (IC50 = 895.09 ± 2.04 μM). In chapter four, procedures for different biological assay are described.