Dithiocarbamates effectively inhibit the β-carbonic anhydrase from the dandruff-producing fungus Malassezia globosa

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• 作者：Daniela Vullo^a ; Sonia Del Prete^b ; ^c ; Alessio Nocentini^b ; Sameh M. Osman^d ; Zeid AlOthman^d ; Clemente Capasso^c ; Murat Bozdag^a ; Fabrizio Carta^b ; Paola Gratteri^e ; Claudiu T. Supuran^b ; ^d ; ^{claudiu.supuran@unifi.it}
• 关键词：Carbonic anhydrase ; β-CA-class enzyme ; Dithiocarbamate ; Inhibitor ; Malassezia globosa
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1260-1265
• 全文大小：1189 K
• 卷排序：25

文摘

A series of dithiocarbamates (DTCs) was investigated for the inhibition of the β-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa, MgCA, a validated anti-dandruff drug target. These DTCs incorporate various scaffold, among which those of N,N-dimethylaminoethylenediamine, the aminoalcohols with 3–5 carbon atoms in their molecule, 3-amino-quinuclidine, piperidine, morpholine and piperazine derivatives, as well as phenethylamine and its 4-sulfamoylated derivative. Several DTCs resulted more effective in inhibiting MgCA compared to the standard sulfonamide drug acetazolamide (KI of 74 μM), with KIs ranging between 383 and 6235 nM. A computational approach, involving a homology modeling of the enzyme and docking inhibitors within its active site, helped us rationalize the results. This study may contribute to better understand the inhibition profile of MgCA, and offer new ideas for the design of modulators of activity which belong to less investigated chemical classes, thus potentially useful to combat dandruff and other fungal infections.