4-Substituted Benzenesulfonamides Incorporating Bi/Tricyclic Moieties Act as Potent and Isoform-Selective Carbonic Anhydrase II/IX Inhibitors

Abstract

As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (4-6) featuring the primary benzenesulfonamide moiety linked to bi/tricyclic scaffolds were investigated. Highly effective inhibitors against the target tumor-associated hCA IX (low nanomolar/subnanomolar potency levels) showing significant functional selectivity profile toward hCA I, II, and IV isozymes were identified. Molecular docking studies clarified the reasons behind the activity and selectivity of the new compounds.

Novel 2-substituted-benzimidazole-6-sulfonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IX and XII and molecular docking studies

“…To clarify the reasons for the activities displayed by the newly designed compounds, molecular docking studies were attained. Docking calculations were performed using a protocol already successfully applied in our previous work on CA inhibitors 39 . Namely, AutoDock4.2 (AD4) 30 , 37 was employed together with the AutoDock4(Zn) forcefield 31 , which was specifically designed to accurately predict the binding interactions of ligands docking to zinc metalloproteins.…”

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

“…Due to the established role of CA IX/CA XII in cancer, many classes of potent and selective CA IX/CA XII inhibitors have been developed which have shown promising activity in in vitro as well as in vivo models. Many researchers have put their effort to develop potent CA IX/CA XII inhibitors, which selectively inhibit CA IX/CA XII or both over the cytosolic CA isoforms 269–316 …”

“…It was >1370‐, 577‐, and 990‐fold selective for hCA IX over hCA I, hCA II, and hCA IV. The molecular docking study indicated that pyrimidine ring nitrogen of compound 304 actively participated to establish H‐bond interaction with Q71 and Q92 side chains, which may be provided favorable binding with hCA IX led to achieving high affinity for hCA IX 311 . Bozdag et al developed 2‐aminophenol‐4‐sulfonamide and its urea analogues by modifying lead molecule SLC‐0111as potent hCA IX/hCA XII inhibitors.…”

“…The molecular docking study indicated that pyrimidine ring nitrogen of compound 304 actively participated to establish H-bond interaction with Q71 and Q92 side chains, which may be provided favorable binding with hCA IX led to achieving high affinity for hCA IX. 311 (Figure 21) was the most effective and selective derivative which displayed a K i value of 17.7 and 7.4 nM for hCA IX and hCA XII, respectively, a K i value of >10 000 nM was shown by this derivative for hCA I as well as hCA II. In psoralen-benzenesulfonamide series compound 308 (Figure 21) Figure 21) have demonstrated the most effective inhibition toward hCA IX (K i value of 8.2, 9.6, 8.5 nM, respectively) and hCA XII (K i value of 5.6, 5.8, and 7.1 nM, respectively).…”

Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

“…Each inhibitor was tested in triplicate, in serial dilutions starting from 0.01 to 0.1 mM. An incubation time of 15 min between inhibitor and enzyme has been used, as reported earlier, in order to be sure that the enzyme-inhibitor complex has been formed [2,25,27,[39][40][41][42][43][44][45][46][47][48][49][50]. The inhibition constants were obtained by using the Cheng-Prusoff equation [39,[51][52][53] and are the mean from three determinations.…”