Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular age
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ORIGINAL ARTICLE
Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents Ashutosh Prasad Tiwari1 · B. Sridhar2 · Helena I. Boshoff3 · Kriti Arora3 · G. Gautham Shenoy1 · K. E. Vandana4 · G. Varadaraj Bhat1 Received: 4 June 2019 / Accepted: 24 August 2019 © Springer Nature Switzerland AG 2019
Abstract Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4–7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development. Graphic abstract
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-019-09990-z) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
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Molecular Diversity
Keywords TB · Diphenylether · InhA · Molecular docking · Correlation study · Antitubercular
Introduction Tuberculosis (TB) is the major cause of death from a single infectious agent (above HIV/AIDS). It is also one among leading 10 causes of death [1]. About 1.3 million deaths among HIV-negative and an additional 0.3 million in HIVpositive people in 2017 were due to TB. Though this indicates the overall results of all countries and age groups, 90% of them were adults (age ≥ 15 years), in the most productive years of their life. Millions of deaths are prevented each year, about 54 million in 2000–2017, with timely diagnosis and treatment [2]. The success rates of treatment for the new cases are around 82% globally, as indicated by latest data of the treatment outcome in 2016. TB treatments take too long to cure and can be toxic. They are also complicated to administer which results in poor patient compliance [3]. New treatments that are faster, simpler and affordable are urgently needed. A validated target for Mycobacterium is enoyl-acyl carrier protein
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