Abstract
A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a–j were synthesized in good yield from the key compound 4-(benzyloxy)-N′-(substituted benzylidene) benzo hydrazide, called Schiff ’s bases 5a–j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a–j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski’s rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a–j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.
Highlights
Tuberculosis (TB) is one of the life threating disease caused by Mycobacterium tuberculosis (MTB), which has shown advanced mechanisms to evade host defense
Based on the report published by World Health Organization (WHO), globally 1.5 million people died and approximately 9 million people were diagnosed with TB in 2015 [1,2,3,4], and the number of new infected cases has continually been on rise up to 2018
We have developed an ecofriendly and efficient ultrasound assisted protocol for synthesis of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a–j
Summary
Tuberculosis (TB) is one of the life threating disease caused by Mycobacterium tuberculosis (MTB), which has shown advanced mechanisms to evade host defense. Decades after the discovery of MTB, TB remains a major cause of morbidity and mortality in many developing countries. The long duration of therapy and side effects of existing anti-tubercular drugs [5,6] leads to failure to cure TB and results in highly lethal, extremely expensive, and complicated to treat [7,8,9] conditions such as multi-drug resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). A more dangerous and incurable form of TB known as totally drug resistant tuberculosis (TDR) has been reported [10,11,12,13]. It is crucial to develop new drugs which will effectively treat MDR and XDR tuberculosis conditions and reduce the complexity and duration of the current therapeutic treatment
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