Hologram- and descriptor-based QSAR studies for a series of non-azoles derivatives active against C. neoformans

• Author(s): Cunha, Lara B. ; Freitas, Humberto F. ; Castilho, Marcelo Santos ; Cunha, Lara B. ; Freitas, Humberto F. ; Castilho, Marcelo Santos
• Date: 2014
• Origin: Oasisbr
• Subject(s): Antifungal; Non-azole; Chemometrics; 2D QSAR; HQSAR
• Document Type: Journal article
• Language: English

Description

p. 1623-1634

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Over the last decades fungal infections have become an increasing health problem, especially for immunocompromised patients. Unfortunately, the gold standard prophylactic therapy for such ailment is based on azole derivatives, which are fungistatic rather than fungicidal against C. neoformans and cause hepatotoxicity. Aiming at circumvent these problems, non-azole CYP51 inhibitors were designed. Herein a comprehensive structure-activity relationships study was carried out for a dataset of 110 molecules by means of hologram– and descriptor–based QSAR studies. The best descriptor-based QSAR model (r2 = 0.92, q2 = 0.90, 6 LVs and r2pred = 0.86) suggests that resonance effects (ESpm08r) play a major role for antifungal activity. The hologram-based QSAR (r2 = 0.87, q2 = 0.81, 6 LVs and r2pred = 0.84) supports this hypothesis and hints at steric properties that should also contribute to non-azole inhibitors potency. The insights provided by the integrated analysis of QSAR models, along with their good predictive power prove their usefulness to future drug design efforts.