title: The antifungal activity of 2,2'-diamino-4,4'-dithiazole derivatives is due to the possible inhibition of lanosterol-14-alpha-demethylase.
abstract: Aryl/alkyl sulfonylamido-, arylsulfenylamido-, arylcarboxamido- and ureido/thioureido/guanidino derivatives of 2,2'-diamino-4,4'-dithiazole were prepared by reaction of the title compound with sulfonyl/sulfenyl halides, sulfonic acid anhydrides, acyl chlorides, tosyl isocyanate, aryl/allyl isocyanates or isothiocyanates. Mono- as well as bis-derivatized compounds have been obtained. Several of the newly synthesized compounds act as effective antifungal agents against Aspergillus and Candida spp., some of them showed activities comparable to ketoconazole (with minimum inhibitory concentrations in the range of 0.2-1.8 microg/mL) but possessed lower activity as compared to itraconazole. Greatest activity was detected against A. niger, and least activity against C. albicans. The mechanism of action of these compounds probably involves inhibition of ergosterol biosynthesis, and interaction with lanosterol-14-alpha-demethylase (CYP51A1), since reduced amounts of ergosterol were found by means of HPLC in cultures of the sensitive strain A. niger treated with some of these inhibitors. Thus, the compounds reported here and the azole antifungal derivatives might possess a similar mechanism of action at molecular level.
authors.affiliation: Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Firenze Italia.
authors.forename: A
authors.initials: A
authors.lastname: Scozzafava
authors.forename: A
authors.initials: A
authors.lastname: Nicolae
authors.forename: O
authors.initials: O
authors.lastname: Maior
authors.forename: F
authors.initials: F
authors.lastname: Briganti
authors.forename: C T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001234:Aspergillus niger / Q000187:drug effects / Q000201:enzymology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004875:Ergosterol / Q000096:biosynthesis; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D058886:Sterol 14-Demethylase; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D013844:Thiazoles; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D004875:Ergosterol