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.

2-Aminobenzothiazole derivatives: Search for new antifungal agents

“…Moreover, the importance of CYP51 as a plausible target in the treatment of C. albicans infections has been already and successfully reported [23e25]. On the basis of this evidence, compounds 1bei were therefore docked into the catalytic site of the homology based model of C. albicans CYP51 (CA-CYP51) [26,27] which has already been successfully used in a previous study on antifungal agents [7]. Docking binding poses highlighted some interesting features that might be in charge of the antifungal activity of the 4-ClePheO compounds under study.…”

Synthesis and antifungal activity of new hydrazide derivatives

“…A major obstacle in the treatment of C. albicans infections is the spread of antifungal drug resistance mainly in patients chronically subjected to antimycotic therapy, i.e. those treated with broad-spectrum antibiotics, immunosuppressive agents, anticancer, antifungal and anti-AIDS drugs 3,4 . As known, not only biochemical similarity of the human cell and fungi forms is a handicap for selective activity, but also the easily gained resistance is the main problem encountered in developing safe and effective antifungals.…”

Studies on hydrazone derivatives as antifungal agents

“…A major obstacle in the treatment of C. albicans infections is the spread of antifungal drug resistance mainly in patients chronically subjected to antimycotic therapy, i.e., those treated with broad-spectrum antibiotics, immunosuppressive agents, anticancer, and anti-AIDS drugs [1].…”

“…Azole and non-azole antifungal agents are usually used to treat Candida infections, but despite the good antifungal activities observed in vitro, candidemia is still a major cause of death [1]. Many valid therapy programs fail because of widespread secondary C. albicans infections.…”