Toxicity evaluation of sulfamides and coumarins that efficiently inhibit human carbonic anhydrases

Here, we report a toxicity study, conducted on zebrafish larvae, of a series of coumarin and sulfamide compounds that were previously reported as inhibitors of human (h) metalloenzymes, carbonic anhydrases (CAs, EC 4.2.1.1). Due to the high relevance of hCA inhibitors as theragnostic agents, it is of pivotal importance to address safety issues that may arise from the initial in vivo toxicological assessment using zebrafish, a relevant model for biomedical research. None of the reported compounds showed adverse phenotypic effects or tissue damage on developing zebrafish larvae after 5 days of exposure. Our study suggests that the coumarin and sulfamide derivatives considered here are safe and suitable for further development and testing

New Ligandless C−H Activation Procedure for The Decoration of C‐3 Position of 1H‐Indazole Derivatives

Arylation of heteroaromatic rings is one of the most important strategy for the chemical space exploration (e.g. applied in medicinal chemistry). In the last two decades C H activation reactions emerged as powerful and more sustainable synthetic methods for this kind of functionalization if compared to the classical Pd-catalysed cross-coupling reactions (e. g. Suzuki, Stille, Negishi, Hiyama). A further step in the direction of greater sustainability has been done developing ligandless C H activation procedures with higher appeal for industrial applica- tion. Among the various N-based heterocycles exploited in medicinal chemistry, there is no reported ligandless C H activation for 1H-indazole core, although its potential pharma- ceutical applications. In this work we describe a novel synthetic procedure for the direct arylation/heteroarylation of C-3 position of 1H-indazole which was optimized using the Design of Experiment (DoE) (yield up to 72 %) and confirmed a fulfilling robustness among various aryl/heteroaryl and indazole scopes

Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action

© 2020 American Chemical Society. The design of three dual-tailed sulfonamide series 11a-11g, 14a-14h, and 16a-16e as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds 11a-11g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (Ki in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds 11b-11d and 11g were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide

Synthesis of novel benzenesulfamide derivatives with inhibitory activity against human cytosolic carbonic anhydrase I and II and Vibrio cholerae α- and β-class enzymes

The synthesis of a new series of sulfamides incorporating ortho-, meta, and para-benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I and II, and two Vibrio cholerae enzymes, belonging to the α- and β-CA classes (VchCAα, VchCAβ). The compounds were prepared by using the “tail approach”, aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders. The built structure–activity relationship showed that the incorporation of benzhydryl piperazine tails on a phenyl sulfamide scaffold determines rather good efficacies against hCA I and VchCAα, with several compounds showing KIs < 100 nM. The activity was lower against hCA II and VchCAβ, probably due to the fact that the incorporated tails are quite bulky. The obtained evidences allow us to continue the investigations of different tails/zinc binding groups, with the purpose to increase the effectiveness/selectivity of such inhibitors against bacterial CAs from pathogens, affording thus potential new anti-infectives

Novel sulfamide-containing compounds as selective carbonic anhydrase i inhibitors

The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO2NH2) bearing the 1-benzhydrylpiperazine tail and connected by means of a β-alanyl or nipecotyl spacer. All compounds 6a-l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles