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New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties As Carbonic Anhydrase Inhibitors

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New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties As Carbonic Anhydrase Inhibitors pharmaceuticals Article New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties as Carbonic Anhydrase Inhibitors Andrea Angeli 1,2,* , Victor Kartsev 3, Anthi Petrou 4 , Mariana Pinteala 2 , Roman M. Vydzhak 5, Svitlana Y. Panchishin 5 , Volodymyr Brovarets 5, Viviana De Luca 6, Clemente Capasso 6 , Athina Geronikaki 4,* and Claudiu T. Supuran 1 1 Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy; claudiu.supuran@unifi.it 2 Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, 707410 Iasi, Romania; [email protected] 3 InterBioScreen, Chernogolovka, 142432 Chernogolovka, Moscow Region, Russia; [email protected] 4 Department of Pharmacy, School of Health, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; [email protected] 5 Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine 1, Murmanska St, 02094 Kyiv, Ukraine; [email protected] (R.M.V.); [email protected] (S.Y.P.); [email protected] (V.B.) 6 Institute of Biosciences and Bioresources, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy; [email protected] (V.D.L.); [email protected] (C.C.) * Correspondence: andrea.angeli@unifi.it (A.A.); [email protected] (A.G.); Tel.: +30-230-199-7616 (A.G.) Citation: Angeli, A.; Kartsev, V.; Abstract: Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease Petrou, A.; Pinteala, M.; Vydzhak, conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge R.M.; Panchishin, S.Y.; Brovarets, V.; for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic De Luca, V.; Capasso, C.; Geronikaki, and pharmacologic research efforts are underway to achieve the full pharmacological potential of A.; et al. New Sulfanilamide CA modulators of activity. We report here a novel series of sulfanilamide derivatives containing Derivatives Incorporating Heterocyclic Carboxamide Moieties heterocyclic carboxamide moieties which were evaluated as CA inhibitors against the physiological as Carbonic Anhydrase Inhibitors. relevant isoforms hCA I, II, IX, and XII. Some of them showed selectivity toward isoform hCA II and Pharmaceuticals 2021, 14, 828. https:// hCA XII. Molecular docking was performed for some of these compounds on isoforms hCA II and doi.org/10.3390/ph14080828 XII to understand the possible interaction with the active site amino acid residues, which rationalized the reported inhibitory activity. Academic Editors: Susanna Nencetti, Nicolo Tonali and Lidia Ciccone Keywords: carbonic anhydrase; metalloenzymes; inhibitors; molecular docking Received: 19 July 2021 Accepted: 19 August 2021 Published: 23 August 2021 1. Introduction Carbonic anhydrases (CAs) are a ubiquitous metalloenzyme family present in both Publisher’s Note: MDPI stays neutral eukaryote and prokaryote organisms [1]. To date, were discovered eight evolutionarily with regard to jurisdictional claims in unrelated gene classes encoded as α-, β-, γ-, δ-, ζ-, η-, θ-, ι-CAs [2–8]. All these enzymes published maps and institutional affil- − + iations. promoting the hydration of carbon dioxide (CO2) to bicarbonate (HCO3 ) and protons (H ) following a two-step catalytic mechanism [9]. In humans, all CAs belong to the α-class with fifteen isoforms differing by molecular features, oligomeric arrangement, cellular localiza- tion, distribution in organs and tissues, expression levels, kinetic properties, and response to different classes of inhibitors [10–12]. To date, twelve catalytic active isoforms (CA Copyright: © 2021 by the authors. I−IV, VA−VB, VI−VII, IX, and XII−XIV) are known, with a variable CO2 hydrase activity, Licensee MDPI, Basel, Switzerland. which play pivotal roles in a variety of physiological processes connected to pH and CO This article is an open access article 2 homeostasis, respiration, electrolyte secretion, biosynthetic reactions (i.e., gluconeogenesis, distributed under the terms and conditions of the Creative Commons lipogenesis, and ureagenesis), bone resorption; calcification; and tumorigenicity [13]. On Attribution (CC BY) license (https:// the other hand, abnormal levels or activities of these enzymes have been often associated creativecommons.org/licenses/by/ with different human diseases, some of which have been clinically exploited and vali- 4.0/). dated as therapeutic targets for the treatment or prevention of various pathologies such Pharmaceuticals 2021, 14, 828. https://doi.org/10.3390/ph14080828 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 19 Pharmaceuticals 2021, 14, 828 2 of 19 clinically exploited and validated as therapeutic targets for the treatment or prevention of various pathologies such as glaucoma, edema, neurological disorders, epilepsy and more asrecently glaucoma, in cancer edema, [14–16]. neurological In this disorders,context, many epilepsy efforts and are more made recently to explore cancer novel [14– 16and]. Inselective this context, Carbonic many Anhydrase efforts are made Inhibitors to explore (CAIs) novel leading and selective compounds Carbonic with Anhydrase potential Inhibitorsbiomedical (CAIs) applications leading compounds[17,18]. Some with of potentialthe CA inhibitors biomedical mentioned applications in [ 17CheMBL,18]. Some are ofpresented the CA inhibitors in Figure mentioned1. in CheMBL are presented in Figure1. FigureFigure 1. 1.Known Known CACA inhibitors.inhibitors. InIn addition, addition,furano- furano- and and thienopyroles thienopyroles have have attracted attracted interest interest of medicinal of medicinal chemists chemists due todue their to their wide wide range range of biological of biological activities, activiti suches, such as antiviral as antiviral [19– 21[19–21],], antimicrobial antimicrobial [22– 24[22–], anticancer24], anticancer [25–27 [25–27],], anti-inflammatory anti-inflammatory [28,29 [28,29],], antidiabetic antidiabetic [30], [30], carbonic carbonic anhydrase anhydrase in- hibitoryinhibitory [31 ].[31]. On On the otherthe other hand, hand, some some sulfonamides sulfonamides also show also anticancer show anticancer [32,33], antimi-[32,33], crobialantimicrobial [34,35], anti-inflammatory[34,35], anti-inflammatory [36,37] antidiabetic [36,37] antidiabetic [38], and antitubercular[38], and antitubercular [39] activities. [39] activities.Taking into account all of the mentioned above, here we report the synthesis of N- (4-sulfamoylphenyl)-4Taking into accountH-thieno[3,2- all of the mentionedb]pyrrole-5-carboxamide above, here we and reportN-(4-sulfamoylphenyl)- the synthesis of N-(4- 4sulfamoylphenyl)-4H-furano[3,2-b]pyrrole-5-carboxamideH-thieno[3,2-b]pyrrole-5-carboxamide derivatives incorporating and N into-(4-sulfamoylphenyl)- one scaffold car- boximide4H-furano[3,2-b]pyrrole-5-carboxamide and sulfonamide moieties. Furthermore, derivatives 6-oxo[1,3]thiazolo[3,2- incorporating intob][1,2,4]triazole one scaffold derivativescarboximide were and also synthesized.sulfonamide The experimentalmoieties. Furthermore, studies were developed6-oxo[1,3]thiazolo[3,2- together with inb][1,2,4]triazole silico techniques, derivatives aimed to proposewere also a reliable synthesized. binding dispositionThe experimental for this classstudies of CAIs.were developed together with in silico techniques, aimed to propose a reliable binding 2. Results and Discussion disposition for this class of CAIs. 2.1. Design and Synthesis of Compounds 2. ResultsThe synthesis and Discussion of target sulfonamides 7a,c-f and 8a-d,f is presented in Scheme1. Inter- mediate esters were obtained by alkylation of the starting compounds 1 [40] or 2 [41] with 2.1. Design and Synthesis of Compounds the appropriate alkyl halides in DMF using sodium hydride as a base. Then, these com- poundsThe were synthesis used without of target additional sulfonamides purification 7a,c-f to and prepare 8a-d,f 4-alkyl-4 is presentedH-furo[3,2- in Schemeb]pyrrole- 1. 5-carboxylicIntermediate acids esters3a,c-f wereand obtained 4-alkyl-4 byH alkylation-thieno[3,2- ofb]pyrrole-5-carboxylic the starting compounds acids 1 4a-d,f[40] or. Acyl2 [41] chlorideswith the appropriate5 and 6 were alkyl obtained halides (with in DMF yields us ofing 50–80%) sodium by hydride the treatment as a base. of Then, carboxylic these acidscompounds3 and 4 withwere thionyl used without chloride additional in toluene. Relativelypurification unstable to prepare compounds 4-alkyl-45 andH-furo[3,2-6 were immediatelyb]pyrrole-5-carboxylic used for the acids further 3a,c-f step and of 4-alkyl-4 preparationH-thieno[3,2- of the N-[4-(aminosulfonyl)phenyl]-b]pyrrole-5-carboxylic acids 4-alkyl-44a-d,f. AcylH-furo[3,2- chloridesb]pyrrole-5-carboxamides 5 and 6 were obtained (with7a,c-f yieldsand N of-[4-(aminosulfonyl)phenyl]-4- 50–80%) by the treatment of alkyl-4carboxylicH-thieno[3,2- acids 3 andb]pyrrole-5-carboxamides 4 with thionyl chloride8a-d,f in toluene.. Relatively unstable compounds 5 and 6 were immediately used for the further step of preparation of the N-[4- (aminosulfonyl)phenyl]-4-alkyl-4H-furo[3,2-b]pyrrole-5-carboxamides 7a,c-f and N-[4- (aminosulfonyl)phenyl]-4-alkyl-4H-thieno[3,2-b]pyrrole-5-carboxamides 8a-d,f. Pharmaceuticals 2021, 14, x FOR PEER REVIEW 3 of 19 Pharmaceuticals 2021, 14, x FOR
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