ABSTRACT
A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-d-xylulose-5-phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+-chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6-16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 - 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.
Subject(s)
Amides/chemical synthesis , Antimalarials/chemical synthesis , Coordination Complexes/chemical synthesis , Magnesium/chemistry , Phosphoric Acids/chemical synthesis , Plasmodium falciparum/drug effects , Antimalarials/pharmacology , Coordination Complexes/pharmacology , Dose-Response Relationship, Drug , Drug Design , Fosfomycin/analogs & derivatives , Fosfomycin/pharmacology , HeLa Cells , Humans , Ligands , Molecular Docking Simulation , Trypanosoma brucei brucei/drug effectsABSTRACT
Synthetic pathways have been developed to access a series of N-benzylated phosphoramidic acid derivatives as novel, achiral analogues of the established Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductase (PfDXR) enzyme inhibitor, FR900098. Bioassays of the targeted compounds and their synthetic precursors have revealed minimal antimalarial activity but encouraging anti-trypanosomal activity - in one case with an IC50 value of 5.4 µM against Trypanosoma brucei, the parasite responsible for Nagana (African cattle sleeping sickness). The results of relevant in silico modelling and docking studies undertaken in the design and evaluation of these compounds are discussed.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Phosphoric Acids/chemical synthesis , Phosphoric Acids/pharmacology , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/pharmacology , Amides/chemistry , Animals , Antimalarials/chemistry , Cattle , Phosphoric Acids/chemistry , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
A series of N2,N2'-bis[4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccino-hydrazides, containing 4-hydroxycoumarin, hydrazine and tartaric acid moieties, have been prepared and examined for possible biological activity. Several of these compounds exhibit promising HIV-1 integrase inhibition (IC50 = 3.5 µM), and anti-T. brucei (32% viability) and anti-mycobacterial (Visual MIC90 = 15.63 µM) activity.
Subject(s)
Antifungal Agents/pharmacology , Antitubercular Agents/pharmacology , Coumarins/pharmacology , HIV Integrase Inhibitors/pharmacology , Hydrazines/pharmacology , Trypanocidal Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/metabolism , Antitubercular Agents/chemical synthesis , Antitubercular Agents/metabolism , Catalytic Domain , Coumarins/chemical synthesis , Coumarins/metabolism , HIV Integrase/chemistry , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/metabolism , HIV-1/enzymology , HeLa Cells , Humans , Hydrazines/chemical synthesis , Hydrazines/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Mycobacterium tuberculosis/drug effects , Protein Binding , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/metabolism , Trypanosoma brucei brucei/drug effectsABSTRACT
A series of novel, substituted 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones have been prepared and shown to exhibit promising concentration-dependent activity against human SH-SY5Y cells, Plasmodium falciparum, Mycobacterium tuberculosis and P. aeruginosa. Substituent effects on observed bioactivity have been explored; the para-fluorophenyl derivative 3d exhibited activity across the range of the bioassays employed, indicating the potential of the 2-chloro-3-[(4-arylthiazol-2-yl)amino]-1,4-naphthoquinone scaffold in the development of novel, broad spectrum therapeutics.
Subject(s)
Naphthoquinones/chemical synthesis , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of readily accessible 4-arylimino-3-hydroxybutanoic acids have been prepared and evaluated as potential HIV-1 Integrase inhibitors. None of the ligands exhibited significant toxicity against human embryonic kidney (HEK 293) cells, while five of them showed activity against HIV-1 integrase - the most active (6c) with an IC50 value of 3.5⯵M. In silico docking studies indicate the capacity of ligand 6c to interact with several amino acid residues and the two Mg2+ cations in the HIV-1 integrase receptor cavity.
Subject(s)
HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , Hydroxybutyrates/pharmacology , Dose-Response Relationship, Drug , HEK293 Cells , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , Humans , Hydroxybutyrates/chemical synthesis , Hydroxybutyrates/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.
Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , HIV-1/enzymology , Quinolones/chemistry , Cell Survival/drug effects , Enzyme Activation/drug effects , HEK293 Cells , HIV Integrase/metabolism , HIV Integrase Inhibitors/metabolism , HIV Integrase Inhibitors/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , Humans , Quinolones/metabolism , Quinolones/pharmacology , Structure-Activity RelationshipABSTRACT
A series of novel and readily accessible N-benzylated (N-arylcarbamoyl)alkylphosphonate esters and related compounds have been prepared as potential antimalarial agents. Bioassays reveal that some of these compounds exhibit promising activity against Plasmodium falciparum, and exhibit no significant growth inhibition of HeLa cells.
Subject(s)
Amides/pharmacology , Antimalarials/pharmacology , Organophosphonates/pharmacology , Aldose-Ketose Isomerases/antagonists & inhibitors , Amides/chemical synthesis , Amides/toxicity , Antimalarials/chemical synthesis , Antimalarials/toxicity , Fosfomycin/analogs & derivatives , Fosfomycin/pharmacology , HeLa Cells , Humans , Organophosphonates/chemical synthesis , Organophosphonates/toxicity , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50⩾3.0µM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50⩾9.6µM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
Subject(s)
Antineoplastic Agents/pharmacology , Cinnamates/pharmacology , Esters/pharmacology , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cinnamates/chemical synthesis , Cinnamates/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Esters/chemical synthesis , Esters/chemistry , HEK293 Cells , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , HeLa Cells , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
(1)H NMR-based kinetic studies have revealed the latent mechanistic complexity of deceptively simple hydrochloric acid-catalyzed reactions of salicylaldehyde-derived Baylis-Hillman adducts. Reactions conducted at 0 °C afforded 2-(chloromethyl)cinnamic acid derivatives as the major products and the corresponding 3-(chloromethyl)coumarin derivatives as the minor products. In reactions conducted in refluxing acetic acid, however, the 3-(chloromethyl)coumarin derivatives are the sole products. Variable-temperature (1)H NMR analysis permitted the determination of the rate constants and kinetic parameters involved in the pseudo-first-order formation of (Z)-2-(chloromethyl)-3-(2-hydroxyphenyl)-2-propenoic acid. The kinetic data clearly preclude the operation of classical kinetic versus thermodynamic control and indicate the operation of three independent reaction pathways. Theoretical studies of these pathways undertaken at the B3LYP/6-31G(d) level permitted rationalization of the experimental data and provided insights into the possible mechanism of the enzymic E-Z isomerization and cyclization of (E)-cinnamic acid analogues to afford coumarins.
ABSTRACT
Novel 3-hydroxy-3-phenylpropanoate ester-azidothymidine (AZT) conjugates have been prepared using Baylis-Hillman methodology, and their potential as dual-action HIV-1 Integrase and Reverse Transcriptase inhibitors has been explored using enzyme inhibition and computer modelling techniques; their activity and HeLa cell toxicity have been compared with those of their cinnamate ester analogues.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Zidovudine/chemistry , Zidovudine/pharmacology , Anti-HIV Agents , HIV Infections/drug therapy , HIV Infections/virology , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , HeLa Cells , Humans , Molecular Docking Simulation , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity Relationship , Zidovudine/chemical synthesisABSTRACT
A series of seven novel, rationally designed N-substituted 3-{3,5-dimethylfuro[3,2-g]coumarin-6-yl}propanamides have been prepared as potential HIV-1 integrase (IN) inhibitors via a five-step pathway commencing with resorcinol and diethyl 2-acetylglutarate, and the HIV-1 IN inhibition potential of these compounds has been examined relative to raltegravir, a known HIV-1 IN inhibitor.
Subject(s)
Furocoumarins/chemistry , Furocoumarins/pharmacology , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Crystallography, X-Ray , HIV Infections/drug therapy , HIV Infections/enzymology , HIV Infections/virology , HIV Integrase/chemistry , HIV Integrase/metabolism , HIV-1/enzymology , Humans , Structure-Activity RelationshipABSTRACT
DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand-receptor interactions.
Subject(s)
Aldose-Ketose Isomerases/antagonists & inhibitors , Aldose-Ketose Isomerases/chemistry , Amides/chemical synthesis , Carbamates/chemical synthesis , Drug Design , Aldose-Ketose Isomerases/metabolism , Amides/chemistry , Amides/pharmacology , Binding Sites , Carbamates/chemistry , Carbamates/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Protein Binding/drug effectsABSTRACT
Baylis-Hillman-derived 3-(benzylaminomethyl)coumarins have been treated, sequentially, with chloroacetyl chloride and propargylamine to afford alkynylated coumarins as substrates for Click Chemistry reactions with azidothymidine (AZT) in the presence of a Cu(I) catalyst. The dual-action HIV-1 protease (PR) and reverse transcriptase (RT) inhibition potential of the resulting N-benzylated cycloaddition products, and a series of non-benzylated analogues, has been explored using saturation transfer difference (STD) NMR, computer modelling and enzyme inhibition techniques.
Subject(s)
Coumarins/chemistry , Coumarins/pharmacology , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Coumarins/chemical synthesis , HIV Infections/drug therapy , HIV Infections/virology , HIV Protease/metabolism , HIV Protease Inhibitors/chemical synthesis , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , Humans , Models, Molecular , Reverse Transcriptase Inhibitors/chemical synthesis , Zidovudine/chemical synthesis , Zidovudine/chemistry , Zidovudine/pharmacologyABSTRACT
The diethyl esters and disodium salts of a range of heteroarylcarbamoylphosphonic acids have been prepared and evaluated as analogues of the highly active DOXP-reductoisomerase (DXR) inhibitor, fosmidomycin. Computer-simulated docking studies, Saturation Transfer Difference (STD) NMR analysis and enzyme inhibition assays have been used to explore enzyme-binding and -inhibition potential, while in silico analysis of the DXR active site has highlighted the importance of including a well-parameterised metal co-factor in docking studies and has revealed the availability of an additional binding pocket to guide future drug design.
Subject(s)
Aldose-Ketose Isomerases/antagonists & inhibitors , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Fosfomycin/analogs & derivatives , Furans/chemical synthesis , Multienzyme Complexes/antagonists & inhibitors , Organophosphonates/chemical synthesis , Oxidoreductases/antagonists & inhibitors , Aldose-Ketose Isomerases/metabolism , Antimalarials/chemistry , Computer Simulation , Drug Design , Fosfomycin/chemistry , Fosfomycin/pharmacology , Furans/chemistry , Furans/pharmacology , Molecular Structure , Multienzyme Complexes/metabolism , Organophosphonates/chemistry , Organophosphonates/pharmacology , Oxidoreductases/metabolism , Protein BindingABSTRACT
Baylis-Hillman reactions of 2-nitrobenzaldehydes with various activated alkenes afford adducts that undergo reductive cyclisation to quinoline derivatives. The chemo- and regioselectivity of cyclisation appears to be influenced by the choice of both the substrate and the reagent system, and competing reactions have been observed.
Subject(s)
Models, Chemical , Quinolines/chemistry , Quinolines/chemical synthesisABSTRACT
The influence of substituents and structure on the 13C NMR spectra of four series of benzoxathiepine derivatives has been investigated. Signal assignments in the 13C NMR spectra have been facilitated by the use of several predictive methods, permitting comparison of their relative efficacy.
Subject(s)
Benzodiazepines/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Magnetic Resonance Spectroscopy/methods , Carbon Isotopes , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Reference StandardsABSTRACT
Evidence is presented which supports the intermediacy of dipolar Baylis-Hillman-type adducts in the synthesis of coumarin and chromene derivatives from the reaction of 2-hydroxybenzaldehydes with methyl acrylate in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO).
ABSTRACT
5-Hydroxy-2-isopropyl-7-methoxychromone (1d), a chromone constituent isolated from the aerial parts of Baeckea frutescens, and four analogues (1a-c and 1e), all of which exhibit toxicity to the brine shrimp Artemia salina, have been prepared from 2',4',6'-trihydroxyacetophenone. High-resolution mass spectrometric analysis has permitted elucidation of the fragmentation patterns exhibited by these systems following electron-impact ionization.