Abstract
The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H37Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.
Highlights
To synthesize highly active antimycobacterialesters, we used hydrazone acid derived from INH (1) and pyruvic acid, 2-(2-isonicotinoylhydrazineylidene)propanoic acid
By modifying the established antitubercular isoniazid scaffold, we have uniquely combined this molecule with other bioactive compounds and their analogues containing hydroxyl and thiol groups to prepare mutually active derivatives
The molecules were linked with bifunctional pyruvic acid to form hydrazone and ester bonds
Summary
Tuberculosis (TB) and COVID-19 are worldwide pandemic infectious diseases that cause the most deaths in the world. Both diseases have similar symptoms such as cough, fever and difficulty breathing. About one-quarter of the world’s population is estimated to be infected with Mycobacterium tuberculosis (Mtb.), the bacteria that give rise to the disease, especially in low-resource countries including regions with high poverty, lacking basic amenities and medical facilities [2]. Anti-TB medicines have been used for decades and strains that are resistant to one or more of the medicines have been documented in every country surveyed. Only 57% of multidrug-resistant (MDR) TB patients are
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