ABSTRACT
A series of thirty eight novel 3-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole and 1-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl/1,4-diazepan-1-yl)-2-(1H-indol-3-yl)substituted-1-one analogues were synthesised, characterised using various analytical techniques and evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two 'wild' strains Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 6.16 to >200µM. Among the tested compounds, 7i, 7y and 7z exhibited moderate activity (MIC=24.03-29.19µM) and 7j exhibited very good anti-tubercular activity (MIC=6.16µM). Furthermore, 7i, 7j, 7y and 7z were found to be non-toxic against mouse macrophage cell lines when screened for toxicity. All the synthesised compounds were docked to pantothenate synthetase enzyme site to know deferent binding interactions with the receptor.
Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Drug Design , Microbial Sensitivity Tests , Molecular Docking SimulationABSTRACT
A series of thirty three novel 6-(piperazin-1-yl)phenanthridine amide and sulphonamide analogues were synthesized, characterized and screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv strain. These compounds exhibited minimum inhibitory concentration (MIC) between 1.56 and ≥50 µg/mL. Out of these derivatives, few compounds 6l, 6r, 7b, 7f, 7g and 7k exhibited moderate activity (MIC = 6.25 µg/mL) and compounds 6b, 6e, 6k, 6n, 7h, 7i and 7n displayed good activity (MIC = 3.13 µg/mL), whereas compounds 6m, 6s and 7d exhibited excellent anti-tubercular activity (MIC = 1.56 µg/mL). In addition, MTT assay was accomplished on the active analogues of the series against mouse macrophage (RAW 264.7) cells to evaluate the toxicity profile of the newly synthesized compounds and selectivity index of the compounds was determined. Additionally, compounds 6b and 7d were docked to the ATPase domain of M. tuberculosis GyrB protein to know the interaction profile and structures of compounds 6b and 7d were further substantiated through single crystal XRD.
Subject(s)
Amides/pharmacology , Antitubercular Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hydrolases/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Phenanthridines/pharmacology , Piperazines/pharmacology , Amides/chemical synthesis , Amides/chemistry , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Cell Line , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrolases/metabolism , Macrophages/drug effects , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/enzymology , Phenanthridines/chemical synthesis , Phenanthridines/chemistry , Piperazines/chemical synthesis , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
In this communication, we synthesized a series of twenty four novel 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole analogues, characterized using various spectroscopic techniques and evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain. The titled compounds exhibited Minimum inhibitory concentration (MIC) between 3.125 and >50 µg/mL. Among the tested compounds, 5c, 6a, 6j and 6p exhibited moderate activity (MIC = 12.5 µg/mL), while 5a and 6i exhibited good activity (MIC = 6.25 µg/mL) and 6b (MIC = 3.125 µg/mL) exhibited very good anti-tubercular activity. In addition, the analogues 5a, 5c, 6a, 6b, 6i, 6j and 6p were subjected to toxicity studies against mouse macrophage (RAW 264.7) cell lines to analyse the selectivity profile of the newly synthesized compounds and selectivity index of the most active compound was found to be >130 indicating suitability of the compound for further drug development. Structure of 6b was further substantiated through single crystal XRD.
Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Drug Design , Isoxazoles/chemistry , Macrophages/drug effects , Mycobacterium tuberculosis/drug effects , Piperazines/chemical synthesis , Piperazines/pharmacology , Tuberculosis/drug therapy , Animals , Cell Proliferation/drug effects , Cells, Cultured , Crystallography, X-Ray , Macrophages/microbiology , Mice , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Tuberculosis/microbiologyABSTRACT
Focus in this Letter is made to design and synthesize a series of nineteen new 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues employing click chemistry and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv. Among the tested compounds, 7f and 7 j exhibited good activity (MIC = 3.125 µg/mL), while 8a displayed excellent activity (MIC = 1.56 µg/mL) against the growth of M. tuberculosis H37Rv. In addition, 7f, 7 j and 8a compounds were subjected to cytotoxic studies against mouse macrophage (RAW264.7) cell lines and the selectivity index values are >15 indicating suitability of compounds for further drug development.
