title: Poly(amidoamine) dendrimers show carbonic anhydrase inhibitory activity against α-, β-, γ- and η-class enzymes.
abstract: Four generations of poly(amidoamine) (PAMAM) dendrimers incorporating benzenesulfonamide moieties were investigated as inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β-, γ- and η-classes which are present in pathogenic bacteria, fungi or protozoa. The following bacterial, fungal and protozoan organisms were included in the study: Vibrio cholerae, Trypanosoma cruzi, Leishmania donovani chagasi, Porphyromonas gingivalis, Cryptococcus neoformans, Candida glabrata, and Plasmodium falciparum. The eight pathozymes present in these organisms were efficiently inhibited by the four generations PAMAM-sulfonamide dendrimers, but multivalency effects were highly variable among the different enzyme classes. The Vibrio enzyme VchCA was best inhibited by the G3 dendrimer incorporating 32 sulfamoyl moieties. The Trypanosoma enzyme TcCA on the other hand was best inhibited by the first generation dendrimer G0 (with 4 sulfamoyl groups), whereas for other enzymes the optimal inhibitory power was observed for the G1 or G2 dendrimers, with 8 and 16 sulfonamide functionalities. This study thus proves that the multivalency may be highly relevant for enzyme inhibition for some but not all CAs from pathogenic organisms. On the other hand, some dendrimers investigated here showed a better inhibitory power compared to acetazolamide for enzymes from widespread pathogens, such as the η-CA from Plasmodium falciparum. Overall, the main conclusion is that this class of molecules may lead to important developments in the field of anti-infective CA inhibitors.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.affiliation: Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Sameh M
authors.initials: SM
authors.lastname: Osman
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Zeid
authors.initials: Z
authors.lastname: AlOthman
authors.affiliation: Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy; Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Del Prete
authors.affiliation: Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.affiliation: Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia; Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D050091:Dendrimers; C104700:PAMAM Starburst; D020033:Protein Isoforms; D013449:Sulfonamides; D002256:Carbonic Anhydrases
keywords: Bacteria; Carbonic anhydrase; Fungi; PAMAM dendrimer; Pathogens; Protozoa; Sulfonamide