Triazole-indole hybrid molecules as antifungal agents: Design, synthesis and biological activity, and beyond

Invasive fungal infections have increased in frequency and severity over the last twenty years as a result of an increasing number of immunocompromised hosts due to cancer chemotherapy, organ and bone marrow transplantation, or therapy against autoimmune and inflammatory disorders. Candida species (spp.) are among the most common pathogens. Candida albicans is the main cause of candidiasis. In addition non-albicans Candida spp. are becoming more and more involved in nosocomial infections. The emergence of resistance to conventional treatments (e.g. fluconazole) make healing successes weaker. It is therefore urgent to continue efforts to develop new antifungal agents. A series of 2-aryl-3-azolyl-1indolyl-propan-2-ols was designed as new analogs of fluconazole by replacing one of its two triazole moieties by an indole scaffold. Two different chemical pathways were developed; the first one included seven steps and the second one only three. The pharmacomodulation works have enabled us to identify a molecule with a strong biological impact on fungi. Numerous experiments progressively confirmed the high potential of this hybrid molecule as antifungal agent. In this presentation, all aspects of medicinal chemistry will be addressed.