New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design.

Oxana Kazakova,Lucreția Udrescu,Adrian Militaru,Anastasiya Petrova,Adrian Voicu,Roxana Racoviceanu,Diane J Ordway,Gregory Robertson,Codruța Șoica,Richard A Slayden,Mihai Udrescu,Jason Cummings,Marius Mioc

doi:10.3390/ijms222212542

Abstract

Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.

Highlights

Introduction conditions of the Creative CommonsDespite the remarkable progress made in the 20th century in terms of prevention and therapeutic approaches, tuberculosis (TB) still remains one of the deadliest diseases worldwide, with devastating personal, social, and economic impacts
Following the resulting data obtained after the mutual information similarity analysis corroborated with the biological antitubercular activity results, we aimed to investigate whether the studied lupane derivatives exhibit rifampicin-like tuberculostatic effect by employing a molecular docking protocol
The obtained results showed that 17 compounds exhibit in vitro antitubercular activity; 6 were highly active on the H37Rv wild type strain, out of which 4 emerged as highly active compounds on three antibiotic mono-resistant H37Rv strains

Summary

Introduction

Introduction conditions of the Creative CommonsDespite the remarkable progress made in the 20th century in terms of prevention and therapeutic approaches, tuberculosis (TB) still remains one of the deadliest diseases worldwide, with devastating personal, social, and economic impacts. World TB Day 2021, commemorated each year on March 24, was “The Clock is Ticking”, sounding an alarm signal that the fight against tuberculosis is not achieving the expected progress [2] This is true in the context of the COVID-19 pandemic, which diverted substantial financial and personnel resources to act against the new threat and put the End TB program at risk (and, in particular, in the most burdened countries). The most thoroughly studied lupane-type pentacyclic triterpenes are betulin, betulinic acid, and lupeol, which were reported as strong chemopreventive and anticancer agents against a large variety of cancer cells [4,5,6,7,8] These compounds exhibit a multitude of additional pharmacological activities, including antimycobacterial effects, which can be exploited in the efforts to fight TB infection [9,10,11]. Other lupane triterpenes active against M. tuberculosis were identified in various plant species: betulinic acid methylenediol ester in Syzygium guineense Wild DC. (Myrtaceae) stem bark [13], two lupane derivatives in Chrysanthemum morifolium (Asteraceae) with selective toxicity on M. tuberculosis [14], 2-O-E-p-coumaroylalphitolic acid, and alphitolic acid in Ziziphus cambodiana [15], and betulone in Alnus incana [16]

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