Abstract
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•A series of quinoline-based sulfonamide hybrids (8a-d, 9a-f, 10a,b and 12) has been designed and synthesized.•Imine has been utilized as an anchor linker elongated between benzenesulfonamide pharmacophores.•The inhibitory activity of all hybrids against hCA isoforms (I, II, IX, and XII) was exploited.•Hybrids 8a and 10b displayed powerful inhibitory activity against all tested hCA isoforms.•Hybrid 10 displayed an excitable activity in MCF-7 cell line under normotic condition with IC50 of 8.42 µM in comparison to the standard staurosporine (IC50 = 5.34 µM) and excellent activity under hypoxic conditions (IC50 = 1.56 µM) in comparable to staurosporine (IC50 = 4.45 µM).•Hybrids 8a and 10b encouraged MCF-7 and MDA-MB-231 cell apoptosis alongside promising Bax/Bcl expression ratio change.
A novel set of quinoline tailored with the sulfonamide as zinc-binding group (ZBG) has been rationalized and synthesized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Such hybrids were decorated by a novel elongated imine linker with/without ethylene spacer with variable hydrophobic and lipophilic pockets. Therefore, a regioisomeric tactic has been established, most of which act as efficient inhibitors of the tumor-associated CA isoforms IX and XII. Interestingly, one hybrid 10b displayed an appreciable activity in MCF-7 cell line under normoxic condition (IC50 of 8.42 µM) in comparison to the standard staurosporine (IC50 = 5.34 µM) and excellent activity under hypoxic conditions (IC50 = 1.56 µM) in comparison to staurosporine (IC50 = 4.45 µM). Furthermore, hybrids 8a and 10b encouraged MCF-7 and MDA-MB-231 cell apoptosis alongside promising Bax/Bcl expression ratio change. Docking studies were also, performed and agreed with the biological results. Our SAR study suggested that our regiosiomerization tactic for the quinoline based-sulfonamide molecules led to effective inhibition of tumuor-relevant hCAs IX/XII.