Synthesis and in silico studies of novel thiophene-celecoxib hybrid with excellent cardiotoxicity and nephrotoxicity safety profiles

Abstract

Herein, there was a target to synthesis innovative 1,3,4-trisubstituted pyrazole compounds as thiophene-celecoxib hybrids that had higher anti-inflammatory activity with lower toxicity. Using 1-(4-(methylsulfonyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carbaldehyde 3, novel scaffolds were constructed. All synthesized thiophene-celecoxib hybrids (3-13a, b) were subjected to in vitro COX-2 assay. Depending on the findings obtained, compounds 4, 6, 8, 9a, 9b, 10b, 11a and 13b (SI = 1.96-19.77) were furthermore instituted for in vivo to estimate the anti-inflammatory activity. The resulting data from carrageenan induced inflammation showed that 4, 6, 8 and 9a and celecoxib showed excellent percentage of edema inhibition (47-67 %) all over 6 h. Consequently, compounds 4 and 9a were evaluated for ulcerogenicity, cardiotoxicity and nephrotoxicity activity. The reduction of measured five cardiac biomarkers (heart index, CK-MB, troponin-I, AST, LDH), and three biomarkers for kidney function (kidney weight index, creatinine level, urea) which were significant more than celecoxib suggested their safety. Moreover, histopathological examination of stomach, heart and kidney tissues proposed their safety. Additionally, in silico predictions of outcomes 4 and 9a were carried out by Molsoft, ProTox 3.0, biotransformer 3.0 and autodock 4.2.6 and showed comparable results. Briefly, compound 4 made a significant contribution in treatment of carrageenan induced paw edema with promising safety profiles.

Keywords: Anti-inflammatory COX-2; Cardiotoxicity; Docking; Nephrotoxicity; Pyrazole.