Novel therapeutic heterocycles as selective cyclooxygenase-2 inhibitors and anti-cancer agents: Synthesis, in vitro bioassay screenings, and molecular docking studies

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A unique class of 1,5-disubstituted tetrazoles was designed and synthesized, and their biological activities as cyclooxygenase (COX) inhibitors and anti-cancer agents were determined experimentally and assessed with molecular docking studies for two isoenzymes COX-1 and COX-2, as well as oncogenic tyrosine kinase bcr/abl enzymes. The structural modifications of this study comprised five different substitutions at the hydroxy group of our model compound 1. All new compounds showed an enhanced inhibition potency toward COX-2 enzyme with no significant inhibition toward COX-1 enzyme. Tetrazole 4 showed not only the highest desirable inhibition potency for both COX-2 enzyme (IC50 = 0.086 µM,) and COX-1 isoenzyme (IC50 = 61 µM), but also the best selectivity for COX-2 enzyme (SI = 714). Azoles 2, 3, and 5 showed a moderate activity against the human breast cancer cell line (MCF-7; IC50 = 40.68 µM, 70.71 µM, and 13.52 µM, respectively), while among the studied compounds only azole 5 showed anti-cancer activity against the human immortalized myelogenous leukemia (K562), (IC50 = 26.88 µM). All investigated compounds displayed no cytotoxicity for the HDFa (Human Dermal Fibroblasts Adult) cell lines (IC50 = >100 µM).