Elaborating 5-(4-chlorophenyl)-1,3,4-thiadiazole scaffold with a p-tolyl sulfonamide moiety enhances cytotoxic activity: Design, synthesis, in vitro cytotoxicity evaluation, radiolabelling, and in vivo pharmacokinetic study

Novel 1,3,4-thiadiazole derivatives (3-5) were designed, synthesized, and screened for cytotoxic activity. Compound 3 bearing substituted benzenesulfonamide scaffold exhibited remarkable potency against breast cancer (MCF-7), hepatoma (HepG2), colon cancer (HCT116), and lung cancer (A549) cells and lower potency on the normal cells (WI-38), as well as, it possesses higher anticancer activity than starting 5-(4-chlorophenyl)-1,3,4-thiadiazole-2-amine (2) and the positive control Staurosporine. The anticancer activity of compound 3 is at least partly attributed to the inhibition of the tumor-associated human carbonic anhydrase isoforms IX and XII. The high selectivity of compound 3 for cancer cells over normal cells and for tumor-associated CA isoforms IX and XII over the off-target cytosolic isoform II reflects its safety. Pharmacokinetic study of compound 3 was evaluated in a normal mice model based on a radiopharmaceutical chemistry approach.