Synthesis and evaluation of biological activities of 1h-benzimidazole derivatives containing some thiazole rings

It is known that increased prostaglandin level is the main cause of inflammation. The cyclooxygenase enzyme is an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and thromboxanes and has two isoforms with 60% similarity to each other. One of the cyclooxygenase isoforms, COX-1, is a constitutive enzyme produced in many tissues, while COX-2 is inducible and responsible for the formation of prostaglandins that cause inflammation. Inhibition of COX-1 causes ulceration by reducing basal production of cytoprotective PGE2 and PGI2. Therefore, complete inhibition of COX-1 is not preferred. Compounds that selectively inhibit the COX-2 enzyme are considered more beneficial anti-inflammatory agents because they carry little or no risk of gastric ulceration. In this master's thesis, some new thiazole derivative compounds, which are possible COX inhibitor and bound to the benzimidazole ring with the hydrazinilidene backbone, were designed; synthesis of these derivatives, evaluation of their structures and in vitro examination of their biological activities were aimed. In order to reach the targeted derivatives, in the first step o-phenylenediamine was reacted with lactic acid and 1H-benzimidazole derivative was reached by cyclocondensation reaction. As a result of the oxidation of the 1-hydroxyethyl group in the 2nd position 2-acetylbenzimidazole compound was reached. Substitution of the alkyl group at position 1 of 1H-Benzimidazole was treated with CH3I/p-fluorobenzyl bromide/p-bromobenzyl bromide. The thiosemicarbazones of 2-acetylbenzimidazole were synthesized by reacting obtained compounds with thiosemicarbazide. In the last step, the resultant thiazole derivatives (6a-e, 7a-e, 8a-e) containing a substituted phenyl ring in the 4th position were reached by the reaction of thiosemicarbazone derivatives containing an alkyl group in the 1st position with -bromoacetophenone derivatives. As a result of the study, a total of 23 compounds were synthesized and 20 of them were original compounds that were not previously recorded in the literature. The structures of these compounds were proven by 1H, 13C NMR and mass analysis. Among the derivatives containing p-substituted benzyl in the 1st position of benzimidazole, the derivatives containing nitro group in the 3rd and 2nd positions of the phenyl ring in the 4th position of the thiazole ring are the most effective derivatives. It was determined that all of the compounds except 6e showed good activity in COX-2 enzyme inhibition and the most effective compound was 8c, and the most effective compounds in COX-1 enzyme inhibition were 7b and 6c. When the inhibitory properties against COX-1 and COX-2 enzymes were compared, it was observed that the compounds obtained inhibited the COX-2 enzyme with much lower IC50 values. This shows that the obtained compounds are more selective to the COX-2 enzyme. When evaluated in terms of ADME parameters, it was observed that there are compounds that can be drug candidates among the synthesized compounds due to their appropriate physicochemical parameters.