QSAR Studies, Synthesis and Antibacterial Assessment of New Inhibitors Against Multidrug-Resistant Mycobacterium tuberculosis.
BACKGROUND
The increasing rate of appearance of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) is a serious problem at the present time. MDR-TB forms do not respond to the standard treatment with the commonly used drugs and can take some years or more to treat with drugs that are less potent, more toxic and much more expensive.


OBJECTIVE
The goal of this work is to identify the novel effective drug candidates active against MDR-TB strains through the use of methods of cheminformatics and computeraided drug design.


METHODS
This paper describes Quantitative Structure-Activity Relationships (QSAR) studies using Artificial Neural Networks, synthesis and in vitro antitubercular activity of several potent compounds against H37Rv and resistant Mycobacterium tuberculosis (Mtb) strains.


RESULTS
Eight QSAR models were built using various types of descriptors with four publicly available structurally diverse datasets, including recent data from PubChem and ChEMBL. The predictive power of the obtained QSAR models was evaluated with a cross-validation procedure, giving a q2=0.74-0.78 for regression models and overall accuracy 78.9-94.4% for classification models. The external test sets were predicted with accuracies in the range of 84.1-95.0% (for the active/inactive classifications) and q2=0.80- 0.83 for regressions. The 15 synthesized compounds showed inhibitory activity against H37Rv strain whereas the compounds 1-7 were also active against resistant Mtb strain (resistant to isoniazid and rifampicin).


CONCLUSION
The results indicated that compounds 1-7 could serve as promising leads for further optimization as novel antibacterial inhibitors, in particular, for the treatment of drug resistance of Mtb forms.
['Kovalishyn|Vasyl|V|', 'Brovarets|Volodymyr|V|', 'Blagodatnyi|Volodymyr|V|', 'Kopernyk|Iryna|I|', 'Hodyna|Diana|D|', 'Chumachenko|Svitlana|S|', 'Shablykin|Oleg|O|', 'Kozachenko|Oleksandr|O|', 'Vovk|Myhailo|M|', 'Barus|Marianna|M|', 'Bratenko|Myhailo|M|', 'Metelytsia|Larysa|L|']
D000995:Antitubercular Agents D008958:Models, Molecular D009169:Mycobacterium tuberculosis D016571:Neural Networks, Computer D021281:Quantitative Structure-Activity Relationship D018088:Tuberculosis, Multidrug-Resistant
QSAR Mycobacterium tuberculosis Drug design Artificial Neural Networks