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In this study, a series of eight hybrid compounds combining the Artesunate core with a sulfonamide moiety were synthesized and evaluated for their inhibition potency against the widely expressed human (<jats:italic>h<\/jats:italic>) CAs I, II and the isoform from <jats:italic>P.\u2005falciparum<\/jats:italic> (<jats:italic>Pf<\/jats:italic>CA). All derivatives demonstrated high inhibition potency against <jats:italic>Pf<\/jats:italic>CA, achieving a <jats:italic>K<jats:sub>I<\/jats:sub><\/jats:italic> value in the sub\u2010nanomolar range (0.35\u2005nM). Two Compounds showed a selectivity index of 4.1 and 3.1, respectively, against this protozoan isoform compared to hCA\u2005II. Three Derivatives showed no cytotoxic effects on human gingival fibroblasts at 50\u2005\u03bcM with a high killing rate against both <jats:italic>P.\u2005falciparum<\/jats:italic> and <jats:italic>P.\u2005knowlesi<\/jats:italic> strains with IC<jats:sub>50<\/jats:sub> in the sub\u2010nanomolar range, providing a wide therapeutic window. Our findings suggest that these compounds may serve as promising leads for developing new antimalarial drugs and warrant further investigation, including activity against antimalarial\u2010resistant strains, mode of action studies, and <jats:italic>in\u2005vivo<\/jats:italic> efficacy assessment in preclinical mouse models of malaria.<\/jats:p>","DOI":"10.1002\/cmdc.202300267","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T03:40:44Z","timestamp":1694490044000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Antimalarial Agents Targeting <i>Plasmodium falciparum<\/i> Carbonic Anhydrase: Towards Artesunate Hybrid Compounds with Dual Mechanism of Action"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-7326","authenticated-orcid":false,"given":"Ilaria","family":"D'Agostino","sequence":"first","affiliation":[{"name":"Department of Pharmacy \u201cG. d'Annunzio\u201d University of Chieti-Pescara  66100 Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1705-6943","authenticated-orcid":false,"given":"Susi","family":"Zara","sequence":"additional","affiliation":[{"name":"Department of Pharmacy \u201cG. d'Annunzio\u201d University of Chieti-Pescara  66100 Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8698-9440","authenticated-orcid":false,"given":"Simone","family":"Carradori","sequence":"additional","affiliation":[{"name":"Department of Pharmacy \u201cG. d'Annunzio\u201d University of Chieti-Pescara  66100 Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"De Luca","sequence":"additional","affiliation":[{"name":"Istituto di Bioscienze e Biorisorse CNR  80131 Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3314-2411","authenticated-orcid":false,"given":"Clemente","family":"Capasso","sequence":"additional","affiliation":[{"name":"Istituto di Bioscienze e Biorisorse CNR  80131 Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4784-1734","authenticated-orcid":false,"given":"Clemens H. 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