Network Analysis Guided Designing of Multi-Targeted Anti-Fungal Agents: Synthesis and Biological Evaluation

During the ongoing pandemic, there have been increasing reports of invasive fungal disease (IFD), par-ticularly among immunocompromised populations. Candida albicans is one of the most common clinical pathogenic microorganisms which have become a serious health threat to population either infected with Covid-19 or on treatment with immunosuppressant's/broad-range antibiotics. Currently, benzothiazole is a well-explored scaffold f or anti-fungal activity, especially mercapto substituted benzothiazoles. It is re-ported that exploring the 2nd position of benzothiazoles yield improved anti-fungal molecules. Therefore, in the current study, a lead optimization approach using a bioisosteric replacement protocol was followed to improve the anti-fungal activity of an already reported benzothiazole derivative, N-(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide. To rationally identify the putative anti-candida targets of this derivative, network analysis was carried out. Complexes of designed compounds and identified putative targets were further analyzed for the docking interactions and their consequent retention af-ter the completion of exhaustive MD simulations. Top six designed compounds were synthesized and evaluated for in-vitro anti-fungal property against Candida, which indicated that compounds 1.2c and 1.2f possess improved and comparable anti-fungal activity to N-(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide and Nystatin, respectively.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

During the ongoing pandemic, there is an increasing number of reports on invasive fungal disease among immunocompromised populations. This study focused on optimizing the anti-fungal activity of a benzothiazole derivative and identified potential targets using network analysis. In vitro evaluation showed that two compounds exhibited improved anti-fungal activity.