Novel thiomorpholine tethered isatin hydrazones as potential inhibitors of resistant

Abstract

Bioorganic Chemistry Volume 115, October 2021, 105133 Novel thiomorpholine tethered isatin hydrazones as potential inhibitors of resistant Mycobacterium tuberculosis Author links open overlay panelSivanandhanKarunanidhiaBalakumarChandrasekaranaRajshekharKarpoormathaHarun M.PatelabFrancisKayambaaSrinivas ReddyMeruguaVishalKumaraSanjeevDhawanaBabitaKushwahaaMavela CleopusMahlalelaa a Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville), Durban 4000, South Africa b R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule) 425405, Maharashtra, India Received 23 May 2021, Revised 22 June 2021, Accepted 26 June 2021, Available online 3 July 2021, Version of Record 27 July 2021.

crossmark-logo https://doi.org/10.1016/j.bioorg.2021.105133 Get rights and content Highlights • Novel thiomorpholine tethered isatins synthesized and evaluated against MTB H37Rv.

• Selected compounds screened against five drug-resistant isolates of MTB.

• 5f displayed potent IC50 1.9 µM against rifampicin-resistant MTB.

• Molecular docking and MD simulations conducted against DNA gyrase B.

Abstract Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.