Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives.
Katharigatta Narayanaswamy VenugopalaNizar A Al-Shar'iLina A DahabiyehWafa HouraniPran Kishore DebMelendhran PillayBashaer Abu-IrmailehYasser BustanjiSandeep ChandrashekharappaChristophe TratratMahesh V AttimaradAnroop Balachandran NairSreeharsha NagarajaPottathil ShinuMichelyne HarounMahmoud KandeelAbdulmalek Ahmed BalgonameRashmi VenugopalaMohamed A MorsyPublished in: Antibiotics (Basel, Switzerland) (2022)
A series of 2,3-dihydroquinazolin-4(1 H )-one derivatives ( 3a - 3m ) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1 H )-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k - 3m . Thus, compounds 3k - 3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.
Keyphrases
- mycobacterium tuberculosis
- multidrug resistant
- drug resistant
- pulmonary tuberculosis
- acinetobacter baumannii
- gram negative
- klebsiella pneumoniae
- escherichia coli
- endothelial cells
- induced apoptosis
- single cell
- molecular docking
- randomized controlled trial
- open label
- molecular dynamics simulations
- clinical trial
- stem cells
- molecular dynamics
- cell cycle arrest
- cystic fibrosis
- climate change
- mesenchymal stem cells
- emergency department
- cell therapy
- replacement therapy
- signaling pathway
- cell death
- risk assessment
- drug induced
- endoplasmic reticulum stress
- biofilm formation
- electronic health record
- staphylococcus aureus
- human health
- structure activity relationship