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1.
Environ Toxicol Pharmacol ; 80: 103454, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32645360

ABSTRACT

The present armamentarium of commercially available antidotes provides limited protection against the neurological effects of organophosphate exposure. Hence, there is an urgent need to design and develop molecules that can protect and reactivate inhibited-AChE in the central nervous system. Some natural compounds like glucose and certain amino acids (glutamate, the anion of glutamic acid) can easily cross the blood brain barrier although they are highly polar. Glucose is mainly transported by systems like glucose transporter protein type 1 (GLUT1). For this reason, a series of non-quaternary and quaternary glycosylated imidazolium oximes with different alkane linkers have been designed and synthesized. These compounds were evaluated for their in-vitro reactivation ability against pesticide (paraoxon-ethyl and paraoxon-methyl) inhibited-AChE and compared with standards antidote AChE reactivators pralidoxime and obidoxime. Several physicochemical properties including acid dissociation constant (pKa), logP, logD, HBD and HBA, have also been assessed for reported compounds. Out of the synthesized compounds, three have exhibited comparable potency with a standard antidote (pralidoxime).


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/toxicity , Cholinesterase Reactivators/chemical synthesis , Imidazoles/chemical synthesis , Oximes/chemical synthesis , Pesticides/toxicity , Animals , Cholinesterase Reactivators/chemistry , Cholinesterase Reactivators/pharmacology , Electrophorus/metabolism , Imidazoles/chemistry , Imidazoles/pharmacology , Kinetics , Molecular Structure , Oximes/chemistry , Oximes/pharmacology
2.
Eur J Med Chem ; 164: 499-516, 2019 Feb 15.
Article in English | MEDLINE | ID: mdl-30622024

ABSTRACT

Allosteric modulators of G-protein-coupled receptors have lately gained significant traction in drug discovery. Recent studies have shown that allosteric modulation of serotonin 2C receptor (5-HT2C) as a viable strategy for the treatment of various central nervous system (CNS) disorders. Considering the critical role of 5-HT2C in the modulation of appetite, a selective positive allosteric modulator (PAM) of 5-HT2C offers a new opportunity for anti-obesity therapeutic development. In this study, phenyl cyclopropyl-linked N-heterocycles were synthesized and evaluated at 5-HT2C for agonist and PAM activity. Our study shows that imidazole linked phenyl cyclopropyl methanones has PAM activity on both 5-HT2C and serotonin 2B receptor (5-HT2B). Interestingly, piperazine linked phenyl cyclopropyl methanones (58) was active as PAM of 5-HT2C (increased the Emax of 5-HT to 139%), and as negative allosteric modulator (NAM) of 5-HT2B (decreases EC50 of 5-HT 10 times without affecting Emax). Similar effect of compound 58 was observed with synthetic orthosteric agonist lorcaserin on 5-HT2B. Molecular docking study revealed that all active compounds were binding to the predicted allosteric site on 5-HT2C and shared a common interacting residues. Finally, compound 58 suppressed food intake in Sprague Dawley (SD) rats similar to lorcaserin after i.c.v. administration. Therefore, these results suggest that piperazine moiety is essential for dual activity (PAM & NAM) of compounds 58, and supports the hypothesis of 5-HT2C PAM for the treatment of obesity similar to the full agonist.


Subject(s)
Allosteric Regulation/drug effects , Heterocyclic Compounds/pharmacology , Piperazine/pharmacology , Receptor, Serotonin, 5-HT2B/drug effects , Receptor, Serotonin, 5-HT2C/drug effects , Animals , Eating/drug effects , Heterocyclic Compounds/chemical synthesis , Molecular Docking Simulation , Obesity/drug therapy , Piperazine/chemistry , Rats , Rats, Sprague-Dawley
3.
J Org Chem ; 83(24): 14882-14893, 2018 12 21.
Article in English | MEDLINE | ID: mdl-30457336

ABSTRACT

An efficient synthesis of biaryl ethers, from electron-deficient aryl halides using NaH/DMSO under metal- and phenol-free conditions, has been achieved to access dibenzo-bistriazolo-1,4,7-oxadiazonines and vancomycin-like glyco-macrocycles. A 44-membered glyco-macrocycle showed promising activity against vancomycin-resistant Staphylococcus aureus (VRSA).


Subject(s)
Ethers/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Vancomycin/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Chemistry Techniques, Synthetic , Drug Resistance, Bacterial/drug effects , Macrocyclic Compounds/chemistry , Models, Molecular , Molecular Conformation , Oxadiazoles/chemistry , Staphylococcus aureus/drug effects , Vancomycin/pharmacology
4.
Eur J Med Chem ; 82: 106-19, 2014 Jul 23.
Article in English | MEDLINE | ID: mdl-24880230

ABSTRACT

A series of novel γ-(triazolyl ethylidene)butenolides (4-23) were prepared from commercially available l-ascorbic acid in good yields. These butenolides on reaction with ethanolic ammonia/amines led to formation of respective 5-hydroxy pyrrolinones (24-33). The two of these pyrrolinones on dehydration with p-toluenesulfonic acid, were transformed into γ-(triazolyl ethylidene)pyrrolinones (34, 35). Among all the newly synthesized hybrid molecules tested for anticancer activity in vitro, compounds 24, 25, 26, 27, 28, 30 and 32 showed significant activity against MCF-7, MDA-MB-231, PC-3 or U-937 cells. In particular compound 25 (IC50 = 11.3 µM) exhibited most potent activity against breast cancer cells and preliminary studies revealed that potency of this compound is due to ROS generation, subsequent activation of p38, leading to apoptosis and inhibition of cancer cells.


Subject(s)
4-Butyrolactone/pharmacology , Antineoplastic Agents/pharmacology , Pyrrolidinones/pharmacology , Triazoles/pharmacology , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , HEK293 Cells , Humans , MCF-7 Cells , Molecular Structure , Pyrrolidinones/chemical synthesis , Pyrrolidinones/chemistry , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
5.
Eur J Med Chem ; 55: 195-204, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22871486

ABSTRACT

An efficient one pot synthesis of a series of pluripotent (E)-1-(3-methyl-5-aryl-7-styryl-5H-thiazolo[3,2-a]pyrimidin-6-yl)-3-arylprop-2-en-1-ones is reported. It involves reaction of 5-acetyl-6-methyl-4-aryl-dihydropyrimidine-2-thiones, propargyl bromide and aromatic aldehydes in presence of ethanolic KOH. The newly synthesized compounds were evaluated for antimalarial activity against Plasmodium falciparum and as HIV-RT inhibitors. Most of the compound displayed potent antimalarial activity with IC(50)<2 µg/mL. Compounds 6, 11 and 20 showed better activity against P. falciparum K1 strains in comparison to standard drug chloroquine. Compounds 6, 11, and 16 exhibited 73.44, 66.92, and 70.81% HIV-RT inhibition at 100 µg/mL.


Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/toxicity , Antimalarials/chemistry , Antimalarials/toxicity , Chemistry Techniques, Synthetic , Chlorocebus aethiops , HIV Reverse Transcriptase/antagonists & inhibitors , Inhibitory Concentration 50 , Plasmodium falciparum/drug effects , Pyrimidines/chemistry , Pyrimidines/toxicity , Vero Cells
6.
Mini Rev Med Chem ; 12(14): 1497-519, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22827177

ABSTRACT

In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.


Subject(s)
Anti-Infective Agents/chemistry , Antineoplastic Agents/chemistry , Carbohydrates/chemistry , Drug Discovery , Enzyme Inhibitors/chemistry , Glycoconjugates/chemistry , Animals , Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Bacterial Infections/drug therapy , Carbohydrates/pharmacology , Combinatorial Chemistry Techniques/methods , Drug Discovery/methods , Enzyme Inhibitors/pharmacology , Glucosidases/antagonists & inhibitors , Glucosidases/metabolism , Glycoconjugates/pharmacology , Glycopeptides/chemistry , Glycopeptides/pharmacology , Humans , Models, Molecular , Mycoses/drug therapy , Neoplasms/drug therapy , Parasitic Diseases/drug therapy , Virus Diseases/drug therapy
7.
Mol Divers ; 16(2): 335-50, 2012 May.
Article in English | MEDLINE | ID: mdl-22528271

ABSTRACT

Diversity-oriented synthesis of structurally different, novel and small drug like molecules based on 1,4,5-trisubstituted 1,2,3-triazoles is developed in a streamlined sequence of different sets of reactions. The method involves the use of simple, readily available and highly economical substrates and reagents. The molecules developed herein have potential to be exploited either as chemotherapeutic agents or as scaffolds for other biologically active compounds.


Subject(s)
Triazoles/chemical synthesis , Cyclization , Molecular Structure , Oximes/chemical synthesis , Oximes/chemistry , Triazoles/chemistry
8.
J Org Chem ; 77(4): 2001-7, 2012 Feb 17.
Article in English | MEDLINE | ID: mdl-22283925

ABSTRACT

Designing cyclic tetrapeptides (CTPs), which fold into desired structures, is often a challenging task. While it is difficult to synthesize them, they are also prone to adopt multiple conformations. In this paper we report the synthesis and conformational studies of CTP mimics, having nonconstrained α(3)ß motif, that exhibit stable ß- and γ-turn structures. We also demonstrate the transformation of ß-turn to γ-turn structure in similar CTPs by inverting the chirality of ß(3) carbon in C-linked-carbo-ß(3)-amino acid (Caa) from R to S.


Subject(s)
Amino Acids/chemistry , Peptides, Cyclic/chemical synthesis , Drug Design , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Protein Structure, Secondary , Protein Structure, Tertiary
9.
J Enzyme Inhib Med Chem ; 27(2): 211-22, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21657950

ABSTRACT

An economical and efficient one-pot synthesis of a series of novel 5-aryl-6-cinnamoyl-7-methyl-flavanones has been developed by simple refluxing of cinnamoyl chalcones with NaOAc in aqueous ethanol in quantitative yields. These flavanones were screened for their in vitro antioxidant and in vivo antidyslipidemic activities. Among 24 compounds screened, four compounds 28, 29, 30, and 48 showed significant antidyslipidemic activities. However, out of all the compounds, only compound 28 exhibited significant antioxidant activity and other compounds showed moderate antioxidant activities.


Subject(s)
Antioxidants/chemical synthesis , Antioxidants/pharmacology , Flavanones/chemistry , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/pharmacology , Animals , Flavanones/chemical synthesis , Flavanones/pharmacology , Lipids/blood , Male , Molecular Structure , Rats , Structure-Activity Relationship
10.
Carbohydr Res ; 346(10): 1191-201, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21550025

ABSTRACT

A series of pyranosyl homo-C-nucleosides have been synthesized by reaction of butenonyl C-glycosides (5a-5j, and 8) and cyanoacetamide in presence of t-BuOK followed by further modifications. The reaction proceeds by Michael addition of cyanoacetamide to the butenonyl C-glycosides and subsequent dehydrative cyclization and oxidative aromatization to give glycosylmethyl pyridones (6a-6j, 7a-7j, 9, and 10). The glycosylmethyl pyridones (6a-6e) on reaction with POCl(3) under reflux gave respective glycosylmethyl pyridines (11a-11e and 12a-12e) in good yields. The synthesized compounds were screened for their in vitro α-glucosidase, glucose-6-phosphatase and glycogen phosphorylase inhibitory activities. One of the pyridylmethyl homo-C-nucleoside, compound 11d, displayed 52% inhibition of glucose-6-phosphatase as compared to the standard drug sodium orthovanadate while compound 12a showed a significant antihyperglycemic effect of 17.1% in the diabetic rats as compared to the standard drug metformin.


Subject(s)
Enzyme Inhibitors/therapeutic use , Hypoglycemic Agents/chemical synthesis , Nucleosides/chemical synthesis , Pyrans/chemical synthesis , Animals , Cyclization , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucose-6-Phosphatase/antagonists & inhibitors , Glucose-6-Phosphatase/metabolism , Glycogen Phosphorylase/antagonists & inhibitors , Glycogen Phosphorylase/metabolism , Glycoside Hydrolase Inhibitors , Glycosylation , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Models, Chemical , Nucleosides/chemistry , Nucleosides/therapeutic use , Pyrans/chemistry , Pyrans/therapeutic use , Pyridines/metabolism , Pyridones/metabolism , Rats , alpha-Glucosidases/metabolism
11.
Mol Divers ; 15(3): 759-68, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21350965

ABSTRACT

An access to different glycohybrids involving nucleophilic addition of N- and C-nucleophiles to the butenonyl glycosides followed by cyclization and subsequent reactions is reported. In the present communication, three different prototypes, ß-D-glucopyranosylmethyl pyrazolines, ß-D-glucopyranosylmethyl pyrimidines and ß-D-glucopyranosylmethyl biphenyls, were prepared in moderate to good yields.


Subject(s)
Biphenyl Compounds/chemical synthesis , Glucosides/chemistry , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Biphenyl Compounds/chemistry , Molecular Structure , Pyrazoles/chemistry , Pyrimidines/chemistry
12.
Carbohydr Res ; 346(1): 16-25, 2011 Jan 03.
Article in English | MEDLINE | ID: mdl-21129735

ABSTRACT

An efficient synthesis of novel 1,2,3-1H-triazolyl glycohybrids with two or more than two sugar units or a chromenone moiety via copper-catalysed azide-alkyne cycloaddition (CuAAC), a 1,3-dipolar cycloaddition of glycosyl azides to 2,3-unsaturated alkynyl glycosides or propargyloxy coumarins is described. The synthesised glycohybrids were screened for their α-glucosidase, glycogen phosphorylase and glucose-6-phosphatase inhibitory activities. A few of the glycohybrids showed promising inhibitory activities against these enzymes.


Subject(s)
Click Chemistry/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Enzyme Inhibitors/chemistry , Glucose-6-Phosphatase/antagonists & inhibitors , Glycogen Phosphorylase/antagonists & inhibitors , Glycoside Hydrolase Inhibitors , Magnetic Resonance Spectroscopy , Triazoles/chemistry
13.
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
14.
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
15.
Bioorg Med Chem ; 18(13): 4711-20, 2010 Jul 01.
Article in English | MEDLINE | ID: mdl-20605470

ABSTRACT

A series of (2E,2'E)-1,1'-(3-hydroxy-5-methylbiphenyl-2,6-diyl)-bis(3-pheylprop-2-ene-1-ones (5-33) were prepared by the reaction of 1,3-diacetyl biphenyls (1-4) with different aldehydes in presence of catalytic amount of solid KOH in ethanol in excellent yields. The compounds were evaluated for anticancer activity against human breast cancer MCF-7 (estrogen responsive proliferative breast cancer model) and MDA-MB-231 (estrogen independent aggressive breast cancer model) cell lines, HeLa (cervical cancer) cell line, and human embryonic kidney (HEK-293) cells. Most of the compounds preferentially inhibited the growth of the aggressive human breast cancer cell lines, MDA-MB-231 in the range of 4.4-30 µM. The two compounds 9 and 29 proved to be better anticancer agents than the standard drug tamoxifen against the MDA-MB-231 cell lines. Mode of action of these compounds was established to be apoptosis, cell cycle arrest and loss of mitochondrial membrane potential.


Subject(s)
Alkenes/chemical synthesis , Antineoplastic Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Breast Neoplasms/drug therapy , Chalcones/chemistry , Alkenes/chemistry , Alkenes/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Apoptosis , Biphenyl Compounds/chemistry , Biphenyl Compounds/therapeutic use , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/therapeutic use , Female , Humans
16.
Carbohydr Res ; 345(12): 1641-8, 2010 Aug 16.
Article in English | MEDLINE | ID: mdl-20579636

ABSTRACT

[3+2] Cycloaddition of 5-azido-5-deoxy-1,2-O-isopropylidene-alpha-d-xylofuranose with 1,3-diphenyl-prop-3-enones, followed by oxidation of the intermediate triazolines in a tandem manner, led to the regioselective formation of 4-benzoyl-1-(5-deoxy-1,2-O-isopropylidene-alpha-d-xylofuranos-5-yl)-5-phenyl-1H-1,2,3-triazoles in moderate to good yields.


Subject(s)
Azides/chemistry , Chalcones/chemistry , Triazoles/chemical synthesis , Xylose/analogs & derivatives , Cyclization , Molecular Structure , Stereoisomerism , Triazoles/chemistry , Xylose/chemistry
17.
Eur J Med Chem ; 45(6): 2381-8, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20199824

ABSTRACT

A series of 1-phenyl-4-glycosyl-dihydropyridines (4-17 and 19-21) were prepared by the one pot multicomponent reaction of glcosyl aldehyde, beta-keto compounds and aniline or substituted aniline in the presence of TBAHS as catalyst. The compounds were screened in vitro and in vivo for their antileishmanial activities. Most of the compounds exhibited moderate to good activity against amastigotes and promastigotes of Leishmania donovani. The compounds 4, 11, 12, 13, and 17 exhibited potent in vivo activity with selectivity index (SI) values 7.43-18.93. Molecular docking studies with these compounds revealed L. donovani PTR1 as the possible target to show antileishmanial activities.


Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Leishmania donovani/drug effects , Models, Molecular , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Antiprotozoal Agents/metabolism , Antiprotozoal Agents/toxicity , Cell Line , Leishmania donovani/enzymology , Leishmania donovani/growth & development , Life Cycle Stages , Mice , Molecular Conformation , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Pyridines/metabolism , Pyridines/toxicity
18.
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
19.
Bioorg Med Chem Lett ; 19(10): 2699-703, 2009 May 15.
Article in English | MEDLINE | ID: mdl-19362832

ABSTRACT

A simple synthesis of phenyl butenoyl C-glycosides has been achieved by Aldol condensation of peracetylated glycosyl acetones with aromatic aldehydes followed by deacetylation with methanolic NaOMe. The selected butenoyl C-glycosides on conjugate addition of diethyl malonate resulted in polyfunctional alkanonyl glycosides in good yields. The butenoyl C- and alkanoyl C-glycosides were evaluated for their alpha-glucosidase, glucose-6-phosphatse and glycogen phosphorylase enzyme inhibitory activities in vitro. Three of the synthesized (3, 5 and 9) showed potent enzyme inhibitory activities as compared to standard drugs. Compounds 3, 5 and 9 were evaluated in vivo too displaying significant activity as compared to standard drugs acarbose and metformin.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Glucose-6-Phosphatase/antagonists & inhibitors , Glycogen Phosphorylase/antagonists & inhibitors , Glycoside Hydrolase Inhibitors , Glycosides/chemical synthesis , Animals , Blood Glucose/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucose-6-Phosphatase/metabolism , Glycogen Phosphorylase/metabolism , Glycosides/chemistry , Glycosides/pharmacology , Rats , alpha-Glucosidases/metabolism
20.
J Comb Chem ; 11(3): 422-7, 2009.
Article in English | MEDLINE | ID: mdl-19301853

ABSTRACT

A well-organized and efficient approach toward the solution phase synthesis of a library of carbapeptide analogues based on glycosyl amino ester scaffold is described. The reported synthetic route involves a five step preparation of heptofuranuronamides 6a-h and octopyranuronamide 7e from glycosyl amino esters 1 and 7, respectively. Coupling of glycosyl amino esters 1 or 7 with three different N-Fmoc protected amino acids afford the N-Fmoc protected intermediates 2a-c and 7a. Deprotection of Fmoc group in 2a-c and 7a with piperidine gave respective compounds 3a-c and 7b with free amine. Subsequent coupling of 3a-c and 7b with different aromatic acids furnishes respective heptofuranuronates 4a-h and octopyranuronate 7c in good yields. The latter, on ester hydrolysis by LiOH gave the corresponding glycopeptide analogues 5a-h and 7d with terminal carboxyl group. The carboxyl group in these compounds was amidated with oxalyl chloride/ NH(4)OH to afford heptofuranuronamides 6a-h and octopyranuronamides 7e. In vitro screening of all compounds displayed moderate antifungal, antitubercular, and general antibacterial activities. Reverse docking calculations involving over 841 protein drug targets have identified two potential targets for these compounds. These results will form the basis for synthesizing second-generation antimicrobial compounds.


Subject(s)
Anti-Infective Agents/pharmacology , Antifungal Agents/pharmacology , Combinatorial Chemistry Techniques/methods , Glycopeptides/chemical synthesis , Glycopeptides/pharmacology , Amino Acids/chemical synthesis , Amino Acids/chemistry , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Combinatorial Chemistry Techniques/economics , Galactose/chemical synthesis , Galactose/chemistry , Glucose/chemical synthesis , Glucose/chemistry , Glycopeptides/chemistry , Microbial Sensitivity Tests , Models, Molecular , Structure-Activity Relationship
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