Investigation of the carbonic anhydrase inhibitory activity of benzenesulfonamides incorporating substituted fused‐pyrimidine tails

Abstract

Two new series of 2-thiocyclopenta [d]pyrimidine-benzenesulfonamides 12a-l and 2-thiotetrahydroquinazoline-benzenesulfonamides 13a-j were synthesized and evaluated for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory acivity and cytotoxic activity. The derivatives 12a and 12i exerted effective inhibition against CA II with K i = 0.11 and 0.15 µM, while 12a, 12e, 12i, and 13d (K i = 0.083-0.087 µM) were found to be the most potent against CA XII. In addition, higher selectivity toward CA II and CA XII over CA I and CA IX was observed for the majority of the synthesized conjugates. Analysis of the effect of the synthesized compounds on NCI cancer cell lines revealed that compounds 12b and 13d showed mean growth inhibitory effects of 53.59% and 49.25%, respectively. Docking of the synthesized hybrids in the CA II and CA XII binding pockets displayed the capability of the benzenesulfonamide derivatives to form, through their SO 2 NH 2 moiety, the characteristic interactions of the traditional CA inhibitors, besides additional interactions achieved by the tail with isoform-specific residues in the peripheral part of the CA binding sites.

Discovery of novel thioquinazoline-N-aryl-acetamide/N-arylacetohydrazide hybrids as anti-SARS-CoV-2 agents: Synthesis, in vitro biological evaluation, and molecular docking studies

“…Initially, the starting quinazoline 3 was synthesized by the reaction of 1 with CS 2 ( 2 ) in the presence of KOH under reflux [ 28 , 29 ]. Meanwhile, the starting material 6 was synthesized by the condensation of 4 with thiourea ( 5 ) under basic conditions [ 30 , 31 ] ( Scheme 1 ).

Scheme 1 Synthesis of the starting quinazolines 3 and 6

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Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

“…Second, compounds 103(a-o) were reacted with propargyl bromide to produce compounds N-alkyl-3-prop-2-yn-1-ylthio)-5H- [1,2,4]triazino [5,6b] indole derivatives 104(a-o) followed by the reaction with Newly synthesized compounds 105(a-o) were screened for inhibitory activity against human (h) isoforms of CA, hCA I, II, XIII (cytosolic isoforms), and hCA IX (tumor related isoform) by the stopped-flow CO 2 hydrase assay method by taking AAZ as standard drug and it was observed that 105i (X = F, R = -CH (CH 3 ) 2 ) was found to show potent activity against hCA II and hCA XIII with K i values of 7.7 and 34.9 nM, respectively, as compared to AAZ (K i = 12.1 nM) due to the presence of fluoro-group at fifth position of indole moiety and isopropyl group attached to nitrogen of indole ring [34] (Scheme 15). (110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129).…”

“…Their binding energies were found to be in range of −13.16 to −9.57 kcal/mol with CA II as compared to AAZ (−7.74 kcal/mol) and −11.46 to −9.48 kcal/mol with CA XII as compared to AAZ (−7.57 kcal/mol) [111] (Scheme 93). showed good activity against hCA XII with K i value of 29.8 nM [23] (Scheme 94).…”

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

“…Quinazoline is an aromatic heterocyclic scaffold consisting of fused pyrimidine and a benzene ring. The quinazoline motif is considered to be one of the most important heterocyclic ring systems in pharmaceutical chemistry, present in many compounds and endowed with tremendous biological activities [ 9 , 10 , 11 , 12 ]. The quinazoline nucleus and its derivatives were reported to have significant potential as promising enzyme inhibitors ( Figure 1 ).…”