Exploring new Probenecid-based carbonic anhydrase inhibitors: Synthesis, biological evaluation and docking studies.
Novel Probenecid-based amide derivatives, incorporating different natural amino acids, were synthesized and assayed to test their effect on the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII over the ubiquitous isoforms hCA I and II. Most of them presented a complete loss of hCA II inhibition (K(i)s > 10,000 nM) and strong inhibitory activity against hCA IX and XII in the nanomolar range with respect to the parent compound. A residual activity against hCA I was observed for some of them. These biological results have been explained by docking studies within the active sites of the four studied human carbonic anhydrases (with or without the zinc-bound water) and helped us to better comprehend the rationale behind the design of tertiary sulfonamide compounds as potent but atypical inhibitors of specific isoforms of human carbonic anhydrase.
Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. Electronic address: a.mollica@unich.it.
Adriano
A
Mollica
Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
Roberto
R
Costante
Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Vatan Caddesi, 34093 Fatih, Istanbul, Turkey.
Atilla
A
Akdemir
Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
Simone
S
Carradori
Dipartimento di Chimica, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Azzurra
A
Stefanucci
Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
Giorgia
G
Macedonio
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Mariangela
M
Ceruso
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.
Claudiu T
CT
Supuran
D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000737:chemistry; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D006801:Humans; D062105:Molecular Docking Simulation; D011339:Probenecid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; D011339:Probenecid
Molecular modeling; Probenecid; Selective carbonic anhydrase IX inhibitors; Selective carbonic anhydrase XII inhibitors; Tertiary sulfonamides