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1.
Bioorg Med Chem Lett ; 21(15): 4404-8, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21737274

ABSTRACT

An economical and efficient one step synthesis of a series of 8-(arylidene)-4-(aryl)-5,6,7,8-tetrahydro-quinazolin-2-ylamines and 9-(arylidene)-4-(aryl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-2-ylamines by the reaction of bis-benzylidene cycloalkanones and guanidine hydrochloride in presence of NaH has been developed. All the synthesized compounds were evaluated against Mycobacterium tuberculosis H(37)Rv strain and the α-glucosidase and glycogen phosphorylase enzymes. Few of the compounds have shown interesting in vitro activity with MIC up to 3.12 µg/mL against M. tuberculosis and very good inhibition of α-glucosidase and glycogen phosphorylase enzymes. The most potent non toxic compound 40 exhibited about 58% ex vivo activity at MIC of 3.12 µg/mL. The present study opens a new gate to synthesize antitubercular agents for diabetic TB patients. In silico docking studies indicate that mycobacterial dihydrofolate reductase is the possible target of these compounds.


Subject(s)
Antitubercular Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Pyrimidines/chemistry , Quinazolines/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Binding Sites , Computer Simulation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Glycogen Phosphorylase/metabolism , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Models, Molecular , Mycobacterium tuberculosis/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , alpha-Glucosidases/metabolism
2.
Bioorg Med Chem ; 18(23): 8289-301, 2010 Dec 01.
Article in English | MEDLINE | ID: mdl-21041091

ABSTRACT

A series of 4-alkylaminoaryl phenyl cyclopropyl methanones (6a-6u and 8a-8c) were synthesized from 4-fluorochalcones (3a and 3b) by cyclopropanation of double bond followed by nucleophilic substitution of F with different amines. The compounds were screened for their antitubercular and antimalarial activities against Mycobacterium tuberculosis H37Rv and Plasmodium falciparum 3D7 strains in vitro respectively. Several compounds (6a, 6d-6h, 6p, 6q and 8a-8c) exhibited good in vitro antitubercular activities with MIC values 3.12-12.5µg/mL and preferentially inhibited the growth of P. falciparum in vitro (4a, 4c, 6a-6d, 6f, 6s, 8a and 8c) with IC50 as low as 0.080 and 0.035µg/mL and SI values 4975 and 6948, respectively. Molecular docking studies and in vitro evaluation against FAS-II enzymes using reporter gene assays were carried out to elucidate the mode of action of these molecules. Two compounds 4a and 6g showed significant inhibition at 25µM concentration of the compound.


Subject(s)
Antimalarials/chemical synthesis , Antitubercular Agents/chemical synthesis , Chalcones/chemical synthesis , Cyclopropanes/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/toxicity , Antitubercular Agents/chemistry , Antitubercular Agents/toxicity , Binding Sites , Chalcones/chemistry , Chalcones/toxicity , Chlorocebus aethiops , Computer Simulation , Cyclopropanes/chemistry , Cyclopropanes/toxicity , Mycobacterium tuberculosis/drug effects , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Vero Cells
3.
Eur J Med Chem ; 45(12): 5965-78, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20970222

ABSTRACT

A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4'-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones were further reduced to respective methanols. The antitubercular activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have shown minimum inhibitory concentration (MIC) of 3.12 µg/mL, while compounds 14, 25 and 18 have shown MIC of 1.56 µg/mL and 0.78 µg/mL respectively. One of the compounds, cyclopropyl-4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical isolates resistant strains with MIC 12.5 µg/mL. Compound 36 was orally active in vivo in mice against M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in lungs as compared to control on 30th day after infection.


Subject(s)
Antitubercular Agents/pharmacology , Cyclopropanes/pharmacology , Methanol/pharmacology , Mycobacterium tuberculosis/drug effects , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Chlorocebus aethiops , Cyclopropanes/chemical synthesis , Cyclopropanes/chemistry , Female , Macrophages/drug effects , Methanol/analogs & derivatives , Methanol/chemical synthesis , Mice , Microbial Sensitivity Tests , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Vero Cells
4.
Eur J Med Chem ; 45(1): 142-8, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19846238

ABSTRACT

1,4-Disubstituted-1,2,3-triazoles (3-27) have been synthesized by [3+2] cycloaddition of different 2-(azidomethyl)-dihydronaptho(benzo)furans (2a, 2b, 2c and 2d) with different alkynes. All the compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv. Compounds 2a, 7, 9, 12 and 14 exhibited antitubercular activities with MIC ranging from 12.5 to 3.12 microg/ml.


Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Antitubercular Agents/chemistry , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Temperature , Triazoles/chemistry
5.
Eur J Med Chem ; 44(4): 1705-9, 2009 Apr.
Article in English | MEDLINE | ID: mdl-18952325

ABSTRACT

An economical and facile synthesis of alpha,alpha'-(EE)-bis(benzylidene)-cycloalkanones was achieved by the reaction of cycloalkanones with different aromatic aldehydes using ethanolic KOH in good yields. Few of the selected compounds were reduced with NaBH(4) to the respective alpha,alpha'-(EE)-bis(benzylidene)-cycloalkanols. All these compounds and our earlier synthesized cyclohexyl phenyl methanols were evaluated for their antitubercular, antifungal and antibacterial activities. Several compounds displayed moderate antitubercular activity with MIC=12.5-1.56 microg/mL. However, none of the compounds displayed any significant antifungal activity.


Subject(s)
Alcohols/chemical synthesis , Alcohols/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Alcohols/chemistry , Antitubercular Agents/chemistry , Fungi/drug effects , Microbial Sensitivity Tests
6.
Carbohydr Res ; 343(7): 1153-62, 2008 May 19.
Article in English | MEDLINE | ID: mdl-18346719

ABSTRACT

5-azido-5-deoxy-xylo-, ribo-, and arabinofuranoses were prepared by the reaction of the respective 5-O-(methanesulfonyl) or p-toluenesulfonyl derivatives with NaN3 in DMF. The intermediate 5-azido-5-deoxy glycofuranoses on 1,3-cycloaddition with different alkynes in the presence of CuSO4 and sodium ascorbate gave the corresponding sugar triazoles in very good yields. The synthesized sugar triazoles were evaluated for their antitubercular activity against Mycobacterium tuberculosis H37Rv, where one of the compounds displayed mild antitubercular activity in vitro with MIC 12.5 microg/mL.


Subject(s)
Alkynes/chemistry , Antitubercular Agents/chemical synthesis , Azides/chemistry , Carbohydrates/chemistry , Triazoles/chemical synthesis , Antitubercular Agents/pharmacology , Cyclization , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship
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