Synthesis and biological evaluation of sulfamoyl benzamide derivatives as selective inhibitors for h-NTPDases

The aim of this research work is the synthesis of sulfamoyl-benzamides as a selective inhibitor for h-NTPDases. Sulfonamides are synthesized in aqueous medium from chlorosulfonylbenzoic acid while carboxamides are synthesized using carbodiimide coupling decorated with different biologically relevant substituents such as n-butyl, cyclopropyl, benzylamine, morpholine, and substituted anilines. In addition, sulfonamide-carboxamide derivatives were synthesized having the same substituents on either side. These compounds were screened against h-NTPDase activity, a main family of ectonucleotidases. Among the eight discovered isoforms of the h-NTPDases, four isoforms, h-NTPDase1, -2, -3, and -8, are involved in various physiological and pathological functions, for instance thrombosis, diabetes, inflammation, and cancer. The compound N-(4-bromophenyl)-4-chloro-3-(morpholine-4-carbonyl) benzenesulfonamide (3i) was found to be the most potent inhibitor of h-NTPDase1 with an IC50 value of 2.88 +/- 0.13 mu M. Similarly, the compounds N-(4-methoxyphenyl)-3-(morpholinosulfonyl)benzamide (3f), 5-(N-benzylsulfamoyl)-2-chloro-N-(4-methoxyphenyl)benzamide (3j) and 2-chloro-N-cyclopropyl-5(N-cyclopropylsulfamoyl)benzamide (4d) reduced the activity of the h-NTPDases2 with IC50 in submicromolar concentrations. Against the h-NTPDase3, 3i was the potent compound with an IC50 concentration of 0.72 +/- 0.11 mu M. The h-NTPDase8 was selectively blocked by the most potent inhibitor 2-chloro-5-(N-cyclopropylsulfamoyl)benzoic acid (2d) with (IC50 = 0.28 +/- 0.07 mu M). Moreover, the molecular docking studies of the potent inhibitors showed significant interactions with the amino acids of the respective h-NTPDase homology model proteins.

Automated summary

The aim of this research is to synthesize sulfamoyl-benzamides as selective inhibitors of h-NTPDases. Various sulfonamides and carboxamides with biologically relevant substituents were synthesized and screened for their inhibitory activity against h-NTPDases isoforms. The most potent inhibitors were identified for each isoform, and molecular docking studies showed significant interactions with the target proteins.