Issue 30, 2023, Issue in Progress

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

Abstract

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 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 IC50 in sub-micromolar concentrations. Against the h-NTPDase3, 3i was the potent compound with an IC50 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 (IC50 = 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.

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

Supplementary files

Article information

Article type
Paper
Submitted
09 Jun 2023
Accepted
04 Jul 2023
First published
11 Jul 2023
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2023,13, 20909-20915

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

Z. H. Zaigham, S. Ullah, J. Pelletier, J. Sévigny, J. Iqbal and A. Hassan, RSC Adv., 2023, 13, 20909 DOI: 10.1039/D3RA03874B

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements