Designing novel anticancer sulfonamide based 2,5-disubstituted-1,3,4-thiadiazole derivatives as potential carbonic anhydrase inhibitor

A series of sulfonamide derivatives bearing 2,5-disubstituted-1,3,4-thiadiazole (5a-j) have been synthesized. Thiosemicarbazide was reacted with CS2 to get 2-amino-5-mercapto-1,3,4-thiadiazole 1. The intermediate thiadiazole (1) was alkylated by reacting with different halides (2a-c) to afford the alkylated thiadiazoles (3a-c). The title sulfonamide bearing derivatives (5a-j) have been prepared by condensation of sulfonyl chlorides (4a-d) with thiadiazole derivatives (3a-c). The molecular docking studies of target molecules showed strong binding of compounds (5a-j) with target enzyme (PDBID 1V9E) particularly for compound 5f containing fluoro and methoxy groups. The carbonic anhydrase (CA) inhibitory activity showed derivative 5h to be the most potent (IC50 0.60 +/- 0.02 mu M) as compared to acetazolamide (IC50 0.984 +/- 0.12 mu M) used as standard. Free radical scavenging activity was measured using ascorbic acid as a reference. It was observed that just like CA inhibition the compound 5h showed greater free radical scavenging activity than all other target molecules. Enzyme inhibition kinetics (Lineweaver-Burk plots) showed a compound (5h) to inhibit the enzyme by mixed type of inhibition (Ki and Ki' values 2.91 mu M and 3.88 mu M, respectively). Compound 5h was further investigated that a smaller value of Ki than Ki' showed preferred competitive binding over non-competitive manners. The anticancer activity performed against the MCF-7 cell line showed that the compound 5h inhibits 40% cell growth at 125 mu M concentration. The mechanism of anticancer potential was further investigated by DNA binding studies through electrochemical methods. The UV-Vis spectroscopy and Cyclic voltammetry results suggested that 5h was weakly bound to DNA (binding constant 30-32 M-1). It is thus proposed that anticancer activity of 5h may be through carbonic anhydrase inhibition rather than by DNA binding. Our investigations suggested the derivative 5h to serve as a lead structure in designing potentially more active carbonic anhydrase inhibitors. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

A series of sulfonamide derivatives bearing 2,5-disubstituted-1,3,4-thiadiazole have been synthesized and compound 5h has shown potent carbonic anhydrase inhibitory activity and excellent free radical scavenging properties as demonstrated through molecular docking studies and enzyme activity assays.