Novel adamantane-pyrazole and hydrazone hybridized: Design, synthesis, cytotoxic evaluation, SAR study and molecular docking simulation as carbonic anhydrase inhibitors

Abstract

A series of pyrazole derivatives 4, 5, 6, 12, 13, 14 as well as hydrazone derivatives 7, 10, 11 were synthesized starting from adamantane-1-carbohydrazide as the bioactive core. All newly designed adamantane derivates were established by full characterized using different spectroscopic methods. The novel derivatives were investigated for their antitumor activity against three cell line MCF-7, HepG-2 and A549. They displayed good IC50 values ranged between 1.55 to 42.17 µM in comparison to Doxorubicin (IC50 =3.58–8.19 µM). Surprisingly, adamantine derivatives revealed more sensitivity and selectivity to lung cancer cells (A549) with eight compounds (4, 5, 9a, 9b, 9c, 12, 13a and 14c) having IC50 less than or equal ten micromoles. The most promising three adamantane derivatives 9a, 12 and 13a with IC50 values less than 5 µM were selected to study enzymatic assay for isoenzyme hCAIX and hCAXII. Also, pyrazole core 13a and 12 showed higher KI values than hydrazone derivatives 9a with submicromolar between (0.085–0.527 µM), in comparison to Acetazolamide (0.041–0.068 µM). Compound 13a is the most promising derivatives with anti-proliferative (A549) (IC50=1.55 ± 0.08 µM) which showed CAIX/XII inhibitory activity (KI = 0.085 and 0.14 µM), respectively. Finally, molecular docking simulation was performed to determine the binding modes and possible interaction of the adamantane derivatives within the active site of 3IAI and 1JD0 for CAIX / XII respectively with low binding affinity.