Química medicinal

A Rational Approach towards the Development of Human Carbonic Anhydrase Inhibitors as Antiepileptic Agent

Abstract

Kalyan K Sethi, Prasanta K Nayak, Hindol Sarkar and Saurabh M Verma

Antiepileptic activity study considering the MES model and molecular docking studies were performed for a series of previously synthesized dioxoisoindolin benzene sulfonamide derivatives. The reported molecules were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), specifically against the hCA I and II isoforms. To get a better insight of these molecules as potential inhibitors we specifically consider the hCA I (Ki values in the range 159 nM to >10000 nM) and hCAII (Ki values in range 1.7 nM to >10000 nM). The most potential molecule explored in the study was 3-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)benzenesulfonamide (Ki=27.7 nM), 3-chloro-4-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)benzenesulfonamide(Ki=4.9 nM) and 4-((4-nitro-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide (Ki=34 nM) respectively with obtained p-value <0.01 in the MES study and showed higher antepileptic activity than acetazolamide (AZM). Moreover a well defined docking score with RMSD value of 1.8 throws light on their effective binding to the active site of both 1AZM and 1ZFQ respectively.