Abstract
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•A diverse series of 1,2,4-oxadiazole based compounds bearing various substitutions was designed and synthesized.•Initial active molecule OX12 for HCT-116 (IC50 = 11.5 μM) cells and tumor-associated hCAIX (IC50 = 4.23 µM) was further optimized through SAR.•SAR optimized OX27 shown better activities for HCT-116 cells (IC50 = 6.0 µM) and hCAIX (IC50 = 0.74 µM).•OX27 have high binding affinity for CAIX and substantial affinity for HSA.•OX27 increased the levels of ROS, apoptotic proteins, inhibited colonogenic and migration potential of colon cancer cells.
A diverse series of 1,2,4-oxadiazoles based substituted compounds were designed, synthesized and evaluated as anticancer agents targeting carbonic anhydrase IX (CAIX). Initial structure-activity analysis suggested that the thiazole/thiophene-sulfonamide conjugates of 1,2,4-oxadiazoles exhibited potent anticancer activities with low μM potencies. Compound OX12 exhibited antiproliferative activity (IC50 = 11.1 µM) along with appreciable inhibition potential for tumor-associated CAIX (IC50 = 4.23 µM) isoform. Therefore, OX12 was structurally optimized and its SAR oriented derivatives (OX17-27) were synthesized and evaluated. This iteration resulted in compound OX27 with an almost two-fold increase in antiproliferative effect (IC50 = 6.0 µM) comparable to the clinical drug doxorubicin and significantly higher potency against CAIX (IC50 = 0.74 µM). Additionally, OX27 treatment decreases the expression of CAIX, induces apoptosis and ROS production, inhibited colony formation and migration of colon cancer cells. Our studies provide preclinical rational for the further optimization of identified OX27 as a suitable lead for the possible treatment of CRC.