Tuberculosis (TB) remains the most serious infectious disease worldwide and predominantly occurs in developing countries. The annual death from TB caused by Multidrug-Resistant (MDR) and Extensively Drug-Resistant (XDR) Mycobacterium Tuberculosis (MTB) outnumbers Human Immunodeficiency Virus (HIV). Especially, 90% of active disease in MDR-TB occurs within the first two years and nearly all within three years, indicating the difficulties of MDR-TB treatment. The traditional anti-TB drugs such asisoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, kanamycin, amikacin, capreomycin, levofloxacin, ofloxacin have been widely used to treat TB at the doses recommended by the World Health Organization (WHO). However, previous studies suggested that, MDR-TB did not respond to the two most powerful anti-TBdrugs isoniazid and rifampicin. In 2017, there were 558,000 estimated cases of MDR-TB worldwide. Furthermore, the process for developing new Anti-TB drugs with optimal efficacy and safety is still under experimentation. The one option to control the situation presently is to devise new methods that can help in deriving maximum benefits from traditionally available therapeutic agents.

Automated chemical screening approaches, such as High-Throughput Screening (HTS) assays have been used to detect chemicals in a standardized manner. HTS approaches also have been constructed to exploit anti-TB drugs, but limited success has been achieved. For instance, HTS screening approach was used to identify inhibitors of the enzymatic activity of riboflavin synthase and find novel and effective antimicrobial compounds against brucellosis. Recently, phenotypic screening approaches have been considered more relevant for drug repurposing, exceeding those discovered through the molecular target-based approaches. In our library, the molecular HTS model was also constructed to search for inhibitors of iso citrate lyase and 4-diphosphocytidyl-2-C-methylerythritolsynthetase. We showed that most of the inhibitors had no or weak bacteriostatic activity to MTB H37Rv. So, in the current study, a phenotypic screening approach via MTB H37Rv was adopted to screennew anti-TB agents through 150,000 synthetic compounds and a novel arylhydrazone Schiff base compound- 4-amino-5-Hydroxymethyl-2-Methyl-Pyrimidine Phosphate (HMPP) with strong anti bacterial activity was identified. Further, the toxicity, pharmacokinetic properties, and anti-MTB capacities of HMPP in vivo were studied comprehensively, and the results indicated it was a promising candidate.

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Mary Wilson

Editorial office

Journal of Clinical Pharmacology and Toxicology

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