| Summary: | A series of quinoline–uracil hybrids (<b>10a–l</b>) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds <b>10a–l</b> demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound <b>10h</b> displayed the best selectivity profile with good activity. Compound 10d displayed the best activity profile with minimal selectivity. Compound <b>10l</b> emerged as the best congener considering both activity (IC<sub>50</sub> = 140 and 190 nM for hCA IX and hCA XII, respectively) and selectivity (S.I. = 13.20 and 9.75 for II/IX, and II/XII, respectively). The most active hybrids were assayed for antiproliferative and pro-apoptotic activities against MCF-7 and A549. In silico studies, molecular docking, physicochemical parameters, and ADMET analysis were performed to explain the acquired CA inhibitory action of all hybrids. A study of the structure–activity relationship revealed that bulky substituents at uracil <i>N</i>-1 were unfavored for activity while substituted quinoline and thiouracil were effective for selectivity.
|
|---|