Design, synthesis, in silico studies, in vivo and in vitro assessment of pyridones and thiazolidinones as anti-inflammatory, antipyretic and ulcerogenic hits

Abstract

Pyridine derivatives have occupied a unique position in medicinal chemistry. Aseries of 2(1H)-pyridone molecules, bearing a 4-hydroxyphenyl moiety 4, 5, 6a-c,7a-c, 8a-f and 9a,b were synthesized via a one-pot reaction of 2-cyano-N-(4-hydroxyphenyl)acetamide with diketones such as acetylacetone, isatin, ethyl acetoacetate, arylidine malononitriles, or arylidene esters. Additionally, the thiazole moiety has been incorporated instead of the pyridine skeleton through the isothiocyanates in N, N-dimethylformamide to furnish the non-isolable intermediate salt. Upon reaction of the intermediate with ethyl chloroacetate the corresponding 2-cyano-N-(4-hydroxyphenyl)-2-(4-oxo-3-phenylthiazolidine-2-ylidene)-acetamide (11) was afforded as a final product, which further reacted with aromatic aldehydes to produce 12a,b. All novel hybrids were assessed for their in-vitro and in-vivo anti-inflammatory, ulcerogenic, and antipyretic activities demonstrating moderate to high activity against IL-6 ranging from 24.403% to 89.307% when ompaired to Paracetamol and Phenylbutazone as reference drugs. Furthermore, in-silico prediction methodology were considered for predicting the physicochemical drug-likeliness and ADME characteristics of all synthesised compounds as well as the standard reference drugs: paracetamol and phenylbutazone. The docking tests were performed on the most promising IL-6 derivatives 4, 8a, 8b, 8c, 8f, 12b, Paracetamol, and Phenylbutazone, and their docking scores were compared to the scores of the aforementioned standard drugs.