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

: Singh Manmeet, Verma Himanshu, Bhandu Priyanka, Kumar Manoj, Narendra Gera, Choudhary Shalki, Singh Pankaj Kumar, Silakari Om

Publisher: ELSEVIER

: 2023

Journal of Molecular Structure

: JOURNAL OF MOLECULAR STRUCTURE

: J MOL STRUCT

: 134128

: 1272

: 13

: 0022-2860

: 1872-8014

DOI: https://doi.org/10.1016/j.molstruc.2022.134128

: https://doi.org/10.1016/j.molstruc.2022.134128

: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458262/

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.