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 IC 50 value of 2.88 ± 0.13 μM. 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 IC 50 in sub-micromolar concentrations. Against the h -NTPDase3, 3i was the potent compound with an IC 50 concentration of 0.72 ± 0.11 μM. The h -NTPDase8 was selectively blocked by the most potent inhibitor 2-chloro-5-( N -cyclopropylsulfamoyl)benzoic acid (2d) with (IC 50 = 0.28 ± 0.07 μM). Moreover, the molecular docking studies of the potent inhibitors showed significant interactions with the amino acids of the respective h -NTPDase homology model proteins.