Design, Synthesis, and Biological Evaluation of 1,2,3-Triazole-linked triazino[5,6-b]indole-benzene sulfonamide Conjugates as Potent Carbonic Anhydrase I, II, IX, and XIII Inhibitors

Abstract

A series of 1,2,3-triazole-linked triazino[5,6-b]indole-benzene sulfonamide hybrids (6a–6o) was synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against the human (h) isoforms hCA I, II, XIII (cytosolic isoforms), and hCA IX (transmembrane tumor-associated isoform). The results revealed that the compounds 6a–6o exhibited Ki values in the low to medium nanomolar range against hCA II and hCA IX (Kis ranging from 7.7 nM to 41.3 nM) and higher Ki values against hCA I and hCA XIII. Compound 6i showed potent inhibition of hCA II (Ki = 7.7nM), being more effective compared to the standard inhibitor acetazolamide (AAZ) (Ki = 12.1 nM). Compounds 6b and 6d showed moderate activity against hCA XIII (Ki = 69.8 and 65.8 nM). Hence, compound 6i could be consider as potential lead candidate for the design of potent and selective hCA II inhibitors.

1,2,3‐Triazole hybrids as anticancer agents: A review

“…In this respect, various 1,2,3-triazole derivatives have shown significant inhibition of this enzyme in cancer cells. Chinchilli et al [112] have synthesized 1,2,3triazole-linked triazino [5,6-b]indole-benzene sulfonamide hybrids in which compound 115 was the most potent, with inhibition constant (K i ) values of 7.7 nM against hCA II and 34.9 nM against hCA IX.…”

Phthalimide‐tethered isatins as novel poly(ADP‐ribose) polymerase inhibitors: Design, synthesis, biological evaluations, and molecular modeling investigations

“…In this study, novel series of phthalimide-tethered isatins (6a-n, Compounds 2a-b and 8a-c were prepared according to the reported methods. [42][43][44]48,49] The InChI codes of the investigated compounds, together with some biological activity data, are provided as Supporting Information.…”

“…In Scheme 2, isatin 3a or 3d was heated with different alkyl halides 7a-c in DMF and anhydrous K 2 CO 3 to afford N-substituted isatins 8a-d, [48,49] which then condensed with 4/3-aminobenzohydrazides 2a,b producing intermediates 9a-e. Subsequently, phthalic anhydride 5 underwent a reaction with intermediates 9a-e in refluxing glacial acetic acid using anhydrous sodium acetate to yield target compounds 10a-e.…”

Design, synthesis, SAR, and biological evaluation of saccharin‐based hybrids as carbonic anhydrase inhibitors

“…In the second approach, 1,2,4‐oxadiazole was linked to the benzene ring and nitrogen of the saccharin ring. As 1,2,3‐triazole [ 9 ] and 1,2,4‐oxadiazole [ 10 ] are efficient linkers in the design of potent carbonic anhydrase inhibitors, we chose them to achieve better potency of our molecules. In our present study, we report the design, synthesis, and SAR for a panel of saccharin analogs and tested their inhibitory potency against CA I, CA II, CA IX, and CA XII.…”