The crystal structures of 2-(4-benzhydrylpiperazin-1-yl)-<i>N</i>-(4-sulfamoylphenyl)acetamide in complex with human carbonic anhydrase II and VII provide insights into selective CA inhibitor development

aims: To synthesize coumarin-piperazine conjugates as potent and selective CA IX & XII inhibitors background: Carbonic Anhydrase (CA) are a family of metalloenzymes that catalyzereversible interconversion of CO2 and water to bicarbonate. CA Isoforms I, II, IX, and XII are considered physiologically and pharmacologically relevant objective: To synthesize potent and selective CA IX &XII inhibitors. method: A library of 17 coumarin derivatives clubbed with piperazine and benzyl moiety was designed, synthesized and evaluated for its inhibitory effects and selectivity profile towards physiologically and pharmacologically relevant Carbonic Anhydrase (CA) isoforms I, II, IX, and XII. result: All the derivatives were found to be active against tumour associated isoforms IX and XII. The most active compound against hCA (human Carbonic Anhydrase) IX was found to possess a Ki of 229 nM while the one against hCA XII had a Ki of 294.2 nM. Additionally, two of the compounds were found to have exquisite selectivity. They were found to be approximately 20-fold more selective towards hCA IX than XII. The selectivity of the compounds was further investigated via molecular modeling techniques conclusion: Coumarin-piperazine hybrids were identified as potent and selective CA IX & XII antagonists. Molecular modeling techniques provided interesting cues pertaining to observed selectivity. other: NA

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The crystal structures of 2-(4-benzhydrylpiperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide in complex with human carbonic anhydrase II and VII provide insights into selective CA inhibitor development

Abstract: Our studies suggest that the acetamide linker and long tails are suitable structural features to design selective CA inhibitors.

Cited by 2 publications

References 53 publications

Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain

Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain

Coumarin and Piperazine Conjugates as Selective Inhibitors of the Tumor-associated Carbonic Anhydrase IX and XII Isoforms

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