Inhibition Studies on Human and Mycobacterial Carbonic Anhydrases with N-((4-Sulfamoylphenyl)carbamothioyl) Amides

Abstract

A library of structurally diverse N-((4-sulfamoylphenyl)carbamothioyl) amides was synthesized by selective acylation of easily accessible 4-thioureidobenzenesulfonamide with various aliphatic, benzylic, vinylic and aromatic acyl chlorides under mild conditions. Inhibition of three α-class cytosolic human (h) carbonic anhydrases (CAs) (EC 4.2.1.1); that is, hCA I, hCA II and hCA VII and three bacterial β-CAs from Mycobacterium tuberculosis (MtCA1-MtCA3) with these sulfonamides was thereafter investigated in vitro and in silico. Many of the evaluated compounds displayed better inhibition against hCA I (KI = 13.3–87.6 nM), hCA II (KI = 5.3–384.3 nM), and hCA VII (KI = 1.1–13.5 nM) compared with acetazolamide (AAZ) as the control drug (KI values of 250, 12.5 and 2.5 nM, respectively, against hCA I, hCA II and hCA VII). The mycobacterial enzymes MtCA1 and MtCA2 were also effectively inhibited by these compounds. MtCA3 was, on the other hand, poorly inhibited by the sulfonamides reported here. The most sensitive mycobacterial enzyme to these inhibitors was MtCA2 in which 10 of the 12 evaluated compounds showed KIs (KI, the inhibitor constant) in the low nanomolar range.

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“…Mtb possesses three β-CA genes in its genome: Rv1284 (which encodes a protein referred to as MtbCA1), Rv3588c (which encodes MtbCA2), and Rv3273 (which encodes a third enzyme known as MtbCA3) 8 . Mycobacterial β-CAs have been used as targets for developing anti-TB and antimycobacterial agents that are devoid of antimycobacterial resistance 2,9,10,11,12,7 . Inhibiting mycobacterial β-CAs presents an opportunity to identify novel drug targets within the anti-infective categories (such as antifungal and antibacterial agents) that operate through distinct mechanisms of action compared to those of the conventional pharmacological agents currently in clinical use 2,8,9,10,11,12,7 .…”

“…Mycobacterial β-CAs have been used as targets for developing anti-TB and antimycobacterial agents that are devoid of antimycobacterial resistance 2,9,10,11,12,7 . Inhibiting mycobacterial β-CAs presents an opportunity to identify novel drug targets within the anti-infective categories (such as antifungal and antibacterial agents) that operate through distinct mechanisms of action compared to those of the conventional pharmacological agents currently in clinical use 2,8,9,10,11,12,7 . This approach is particularly important, as pathogenic fungi and bacteria have developed varying levels of resistance to these existing drugs over time 6,7,13–15 .…”

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“…The aim was to unveil the relationship between the structural features and the inhibitory profile of the ligands. As the 3D-solved structure of MtCA3 is currently unavailable, we utilized the homology model (HM) previously built in our previous investigations [ 56 , 57 ].…”

“…The homology modelling procedure used the 3D solved structure of β-CA from Synechocystis sp. PCC 6803 (PDB code 5SWC; resolution 1.45 Å) [ 58 ] as a template [ 56 ]. A large number of models were generated using the Prime module of Schrödinger [ 59 ] and the SwissModel platform [ 60 ].…”

“…A large number of models were generated using the Prime module of Schrödinger [ 59 ] and the SwissModel platform [ 60 ]. These models were subjected to loop refinement and quality assessment procedures [ 56 ]. The highest scoring structure of MtCA3 and the crystal structures of CA I (PDB code 2NMX) [ 61 ], CA II (PDB code 3K34) [ 62 ], MtCA1 (PDB code 1YLK) [ 63 ], and MtCA2 (PDB code 2A5V) [ 64 ], downloaded from the Protein Data Bank (RCSB.org) [ 65 ], were prepared using the Protein Preparation module of the Maestro Schrödinger suite [ 60 ].…”