Abstract
Aims: In this study was two noteworthy pharmacophores quinazolin-4(3H)-one and 1,3,4-thiadiazole through methylene bridge were utilized to design, synthesize and characterize some novel 2-methyl quinazolin-4(3H)-one and 6-chloro-2-methyl quinazolin-4(3H)-one tethered S-substituted-1,3,4-thiadiazole-thiol structural analogs respectively as direct Mycobacterium Tuberculosis (MTB) enoyl acyl carrier protein reductase (InhA) inhibitors.
 Study Design: Design of structural analogs of quinazolin-4(3H)-one tethered 1,3,4-thiadiazole-thiol through methylene bridge by functional group modifications in core scaffold followed by computational studies to select promising compounds. Synthesis of some novel compounds, structural characterization and screening of biological activity of the same.
 Methodology: The molecular docking of designed compunds was carried out using schrodinger Glide XP into the active site of MTB InhA with protein data bank code (PDB ID: 2H7M). The interactions were evaluated based on the glide G score compared with reference standard isoniazid. Ten new compounds 7(A1-A10) were synthesized, characterized and screened for their in-vitro antitubercular activity by Microplate Almar Blue Assay (MABA) method followed by cytotoxicity evaluation of compounds 7A4 and 7A10 using Vero cell line.
 Results: All the designed compounds of series 7(A1-A10) had drug-like characteristics and were non-toxic to normal cells. In the molecular docking studies, compounds 7A4, 7A5, and 7A10 demonstrated strong binding affinity in the active region of MTB InhA protein and retained necessary amino acid interaction, similar to co-crystal 2H7M. Synthesized compounds 7(A1-A10) were found to have good antitubercular activity. Out of the series the compounds 7A4 and 7A10 were found to possess excellent antitubercular activity equipotent to reference standard streptomycin with minimum inhibitory concentration (MIC) value of 6.25µg/ml. The cytotoxic potential of compounds 7A4 and 7A10 showed remarkable selectivity index against Vero cell line.
 Conclusion: The findings of this study highlights the importance of tethering two pharmacophoric motifs in one compound to develop novel antitubercular agents that can be exploited as promising leads as direct InhA inhibitors.
Highlights
Tuberculosis is one of the most dangerous infections, claiming the lives of around 1.21 million people worldwide in the year 2019
Fourier-transform infrared spectroscopy (FT-IR) absorption spectra were recorded in KBr pellets on Shimadzu FT-IR spectrometer 8400, νmax in cm-1. 1H and 13C NMR spectra were recorded on a Bruker AscendTM FT-NMR spectrometer 500 using TMS as the internal standard in DMSOd6 solvent
The computational study was carried out first for determination of drug-like molecules, all the designed compounds presented values within an acceptable range for the properties analyzed indicating their potential as drug-like molecules (Table 1) based on Lipinski’s rule of 5. This rule in general is considered to influence good membrane permeability and oral bioavailability associated with filters namely, molecular weight ≤ 500, QlogP ≤ 5, number of hydrogen bond acceptors ≤ 10 and number of hydrogen bond donors ≤ 5
Summary
Tuberculosis is one of the most dangerous infections, claiming the lives of around 1.21 million people worldwide in the year 2019. The long duration of therapy, combined with the microorganism's resistance, has resulted in tuberculosis recurrence, in multidrugresistant (MDR) and extensively drug-resistant (XDR) tuberculosis. Very few drugs are effective against MDR and XDR strains of Mycobacterium tuberculosis. Second-line drugs have been used for many decades are contributing to a rise in emergence of drug-resistant TB. New drugs are urgently needed to reduce the length of treatment and treat drug-resistant strains. The development of compounds that can serve as enzyme inhibitors is the focus of the quest for new entities [1,2,3,4]
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