title: Design, synthesis, and microbiological evaluation of new Candida albicans CYP51 inhibitors.
abstract: In a program aimed at the design and synthesis of novel azole inhibitors of Candida albicans CYP51 (CA-CYP51), a series of azole 1,4-benzothiazines (BT) and 1,4-benzoxazines (BO) were recently synthesized. A morphological study of the enzyme active site highlighted a hydrophobic access channel, and a docking study pointed out that the C-2 position of the BT or BO nucleus was oriented toward the access channel. Here, we report the design, synthesis, and microbiological evaluation of C-2-alkyl BT and BO compounds. In both series, introduction of the alkyl chain maintained and in some cases improved the anti-Candida in vitro activity; however, there was not always a strict correlation between in vitro and in vivo activity for several compounds.
authors.affiliation: Department of Drug Chemistry and Technology and Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Schiaffella
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Lara
authors.initials: L
authors.lastname: Milanese
authors.forename: Anna
authors.initials: A
authors.lastname: Vecchiarelli
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: Donatella
authors.initials: D
authors.lastname: Pietrella
authors.forename: Renata
authors.initials: R
authors.lastname: Fringuelli
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D048588:Benzoxazines; D065607:Cytochrome P-450 Enzyme Inhibitors; D005656:Fungal Proteins; D013843:Thiazines; C465525:cytochrome P-450 CYP51, Candida albicans; D003577:Cytochrome P-450 Enzyme System