During the past two decades, the frequency of invasive and systemic fungal infections has increased dramatically due mainly to Candida species among which Candida albicans is the most dreadful human pathogen.([i]) Although several antifungal agents such as amphotericin B and the azoles are available, the limitations of current antifungal drugs, increased incidence of systemic fungal infections, and rapid development of drug resistance have highlighted the need for the discovery of new antifungals, preferably with novel modes of action.([ii])

 In the course of our search for prototype antifungal agents from class of thiosemicarbazide derivatives, we identified two isoquinoline-thiosemicarbazides (see Fig.) as promising leads for design of novel small-molecule antifungal agents. The compounds showed inhibitory activity against opportunistic pathogens C. albicans with MIC range of 25-50 µg/mL. More importantly, ortho-methyl derivative displayed antifungal activity at non-cytotoxic concentrations in mammalian cells. Based on docking and molecular modeling studies it was proposed that possible target for antifungal thiosemicarbazide-based compounds is N-myristoyltransferase and ligand recognition process is connected with both structural and electronic parameters such as dipole moment and the highest  occupied  molecular orbital energy.

[i] Giraud F, Guillon R, Logé C, Pagniez F, Picot C, Le Borgne M, Le Pape P. Bioorg Med Chem Letters 19 (2009) 301-304.  

[ii] Babu KS, Li X-C, Jacob MR, Zhang O, Khan SI, Ferreira D, Clark AM. J Med Chem, 49 (2006) 7877-7886 and references therein

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