Schiaffella Fausto, Macchiarulo Antonio, Milanese Lara, Vecchiarelli Anna, Costantino Gabriele, Pietrella Donatella, Fringuelli Renata
Department of Drug Chemistry and Technology and Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
J Med Chem. 2005 Dec 1;48(24):7658-66. doi: 10.1021/jm050685j.
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.
