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1.
Eur J Med Chem ; 92: 415-26, 2015 Mar 06.
Article in English | MEDLINE | ID: mdl-25590862

ABSTRACT

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 Relationship
2.
Eur J Med Chem ; 84: 605-13, 2014 Sep 12.
Article in English | MEDLINE | ID: mdl-25062011

ABSTRACT

A series of twenty six new 1-(4-(2-substitutedthiazol-4-yl)phenethyl)-4-(3-(4-substitutedpiperazin-1-yl)alkyl)piperazine analogues were synthesized by seven steps and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Among the tested compounds, 7j, 7p, and 7r exhibited moderate activity (MIC = 6.25 µg/mL) and compounds 7a, 7f, 7g, 7n and 7v exhibited good activity (MIC = 3.125 µg/mL), while 7h displayed excellent activity (MIC = 1.56 µg/mL) by inhibiting 99% growth of M. tuberculosis H37Rv strain. In addition, all the active compounds were subjected to cytotoxic studies against mouse macrophage (RAW264.7) cell lines and the selectivity index values for most of the compounds is >10 indicating suitability of compounds in an endeavour to attain lead molecule for further drug development.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Design , Mycobacterium tuberculosis/drug effects , Piperazines/chemistry , Piperazines/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Molecular Structure , Piperazines/chemical synthesis , Structure-Activity Relationship
3.
Eur J Med Chem ; 74: 333-9, 2014 Mar 03.
Article in English | MEDLINE | ID: mdl-24486416

ABSTRACT

A series of seventeen new 6-(4-substitutedpiperazin-1-yl)phenanthridine derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv by Microplate Alamar Blue Assay and most active compounds were tested for cytotoxicity studies against mouse macrophage cell lines (RAW264.7). Among the tested compounds, ten compounds exhibited significant activity against the growth of M. tuberculosis (MIC ranging from 1.56 to 6.25 µg/mL). In particular, compounds 5e, 5j and 5k displayed excellent activity against the growth of M. tuberculosis (MIC 1.56 µg/mL). The selectivity index values were found to be >25, indicating compounds likeliness in drug development for tuberculosis. The structure of 5k is substantiated by X-ray crystallographic study. Structure-activity correlation indicates the importance of substituent at 4th position of piperazinyl phenanthridine ring.


Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Phenanthridines/chemical synthesis , Phenanthridines/pharmacology , Animals , Cell Line , Crystallography, X-Ray , Macrophages/drug effects , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/growth & development , Spectrometry, Mass, Electrospray Ionization
4.
Eur J Med Chem ; 71: 324-32, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24333580

ABSTRACT

A series of twenty two novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substitutedpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues were synthesized, characterized ((1)H NMR, (13)C NMR and LCMS) and screened for their in vitro anti-tubercular and antibacterial activity. Many of these compounds exhibited MIC values in the range 7.32-136.10 µM against Mycobacterium tuberculosis H37Rv. Eight compounds were further subjected to cytotoxic studies. Furthermore, the title compounds were screened for antibacterial activity against Staphylococcus aureus ATCC 29213 (gram positive) and Escherichia coli ATCC 25922 (gram negative) bacteria. Many of these compounds exhibited MIC values in the range 0.44-34.02 µM. Compound 3f was found to be the most active with an MIC of 0.44 and 0.8 µM respectively against both the strains. In general, the antibacterial activity of title compounds was more prominent.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Escherichia coli/drug effects , Escherichia coli Infections/drug therapy , Halogenation , Humans , Mycobacterium tuberculosis/drug effects , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Tuberculosis/drug therapy
5.
Bioorg Med Chem Lett ; 23(23): 6292-5, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24138941

ABSTRACT

A series of twenty two novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substituted piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized ((1)H NMR, (13)C NMR and LCMS) and evaluated for their inhibitory activity on the proliferation of human caucasian acute lymphoblastic leukemia cells (CCRF-CEM), breast adenocarcinoma cells (MDA-MB-468) and human colon carcinoma cells (HCT-116). Among all the synthesized ciprofloxacin analogues 3t at 50 µM showed comparable potency to doxorubicin (10 µM) in all three cell lines and 3j inhibited proliferation of MDA-MB-468 up to 35% selectively over other two cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/pharmacology , Fluoroquinolones/chemical synthesis , Fluoroquinolones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Ciprofloxacin/chemical synthesis , Ciprofloxacin/chemistry , Drug Screening Assays, Antitumor , Fluoroquinolones/chemistry , Humans , Molecular Structure , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 23(24): 6805-10, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24169232

ABSTRACT

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.


Subject(s)
Drug Design , Mycobacterium tuberculosis/drug effects , Phenanthridines/chemistry , Phenanthridines/pharmacology , Piperazines/chemistry , Triazoles/chemistry , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Antitubercular Agents/toxicity , Cell Line , Cell Survival/drug effects , Click Chemistry , Mice , Microbial Sensitivity Tests , Phenanthridines/toxicity , Piperazine , Structure-Activity Relationship
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