Benzenesulfonamides Incorporating Hydantoin Moieties Effectively Inhibit Eukaryoticand Human Carbonic Anhydrases

Abstract

A series of novel 1-(4-benzenesulfonamide)-3-alkyl/benzyl-hydantoin derivatives were synthesized and evaluated for the inhibition of eukaryotic and human carbonic anhydrases (CAs, EC 4.2.1.1). The prepared compounds were screened for their hCA inhibitory activities against three cytosolic isoforms as well as two β-CAs from fungal pathogens. The best inhibition was observed against hCA II and VII as well as Candida glabrata enzyme CgNce103. hCA I and Malassezia globosa MgCA enzymes were, on the other hand, less effectively inhibited by these compounds. The inhibitory potency of these compounds against CAs was found to be dependent on the electronic and steric effects of substituent groups on the N3-position of the hydantoin ring, which included alkyl, alkenyl and substituted benzyl moieties. The interesting results against CgNce103 make the compounds of interest for investigations in vivo as potential antifungals.

Click chemistry approaches for developing carbonic anhydrase inhibitors and their applications

“…The antiinfectives based on CAIs started to be seriously considered only in the last decade 90 , and several highly interesting studies for the design of antibacterials 91–93 and antifungals 94–96 which target CAs present in pathogenic organism have emerged. However, in these cases the use of click chemistry has not yet been contemplated, as it is also the situation for CA activators 97 , which might be useful for the management of emotional/fear memory therapy and several cognitive disorders 98 , 99 .…”

Progress of Section “Biochemistry” in 2022

“…A relevant number of papers dealing with this enzyme, its inhibitors, activators and involvement in various diseases have been published in 2022 in this journal [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The first group of contributed materials dealt with the use of this protein for investigations of basic biochemical approaches, such as protein folding [ 7 ], thermodynamic parameters assessment for protein–ligand interactions [ 8 ], bioluminescence resonance energy transfer connected to the binding of the metal ion to apoenzymes [ 9 ], the possibility to evidence chalcogen bonds in the X-ray crystal structures of CA–lig and adduct [ 10 ].…”

“…A large number of CA-related papers dealt with the drug design of CA inhibitors (CAIs) with various applications as anticancer agents (both for treatment and imaging) [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], antineuropathic pain compounds [ 20 ], mountain sickness leads [ 21 ], antiglaucoma agents [ 22 ] or antibacterials with a novel mechanism of action which, unlike classical antibiotics, target bacterial CAs from various pathogens [ 23 , 24 , 25 ]. Both sulfonamide and non-sulfonamide compounds have been reported in these interesting papers, which highly enrich the number of such pharmacological agents useful for the management of a multitude of pathological conditions [ 2 , 3 ].…”

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

“…In this context, over the last decade, several research groups have disclosed that sulfonamide–acyl thiourea derivatives were effective inhibitors of CAs ( Figure 1 b) [ 12 , 13 , 14 , 15 , 16 ]. In order to extend these efforts and in continuation of our interest in the study of sulfonamide CAIs [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], in the present study, we synthesized a panel of 12 structurally diverse N -((4-sulfamoylphenyl)carbamothioyl) amides by the reaction of easily available 4-thioureidobenzenesulfonamide with the appropriate acid chlorides and investigated their inhibitory activities against three human CAs (hCA I, hCA II and hCA VII) and three bacterial β-CAs from Mycobacterium tuberculosis (MtCA1-MtCA3), which were recently validated as effective targets for the development of antituberculosis agents [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ], to discover possible promising drug candidate(s).…”