Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two properties of the aromatic azido group have been exploited in the design of a novel dihydrofolate reductase inhibitor--lipophilicity and biotransformability. 2,4-Diamino-5-(3-azido-4-chlorophenyl)-6-ethylpyrimidine (MZP, 4), which can be prepared in three high-yielding synthetic steps from the antimalarial drug pyrimethamine (1), has a pKa of 7.19, a log P of 2.81 and inhibitory activity against the P388, L1210, B16 and M5076 tumours in vivo. The ethanesulphonic acid salt of MZP (MZPES, 6) is a potent inhibitor of rat liver dihydrofolate reductase (Ki 1.60 nM) and L1210 cells in vitro. Injections of MZPES in water (10 mg ml-1) at pH 4.1 can be sterilised by filtration and are stable provided they are protected from light.
 ...
PMID:The aromatic azido group in anti-cancer drug design: application in the development of novel lipophilic dihydrofolate reductase inhibitors. 344 94

Triazenyl-substituted pyrimethamine derivatives 10a-s have been prepared by coupling diazotized 2,4-diamino-5-(3-amino-4-chlorophenyl)-6-ethyl pyrimidine (1c) with a series of secondary amines in aqueous sodium carbonate solution. The triazenes which are stable and poorly soluble as free bases form more soluble, but unstable, salts with alkanesulfonic acids. The lead dimethyltriazene 2,4-diamino-5[4-chloro-3-(3,3-dimethyltriazen-1-yl)phenyl]-6-et hylpyrimidine (4a) forms a crystalline ethanesulfonic acid salt (solvated with 2-propanol), which is protonated at the pyrimidine N-1 position, as determined by X-ray crystallography. The ability of these new triazenes to inhibit Pneumocystis carinii dihydrofolate reductase in vitro has been compared to that of triazene 4a. The most potent and selective compound, 2,4-diamino-5-[3-[3-[2-(acetyloxy)ethyl]-3-benzyltriazen-1-y l]-4- chlorophenyl]-6-ethylpyrimidine (14a), has an IC50 value of 0.17 microM against the microbial enzyme and potentially useful selectivity (rat liver IC50/P. carinii IC50 = 114).
 ...
PMID:Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase. 919 66

Folate analogue inhibitors of Leishmania major pteridine reductase (PTR1) are potential antiparasitic drug candidates for combined therapy with dihydrofolate reductase (DHFR) inhibitors. To identify new molecules with specificity for PTR1, we carried out a virtual screening of the Available Chemicals Directory (ACD) database to select compounds that could interact with L. major PTR1 but not with human DHFR. Through two rounds of drug discovery, we successfully identified eighteen drug-like molecules with low micromolar affinities and high in vitro specificity profiles. Their efficacy against Leishmania species was studied in cultured cells of the promastigote stage, using the compounds both alone and in combination with 1 (pyrimethamine; 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine). Six compounds showed efficacy only in combination. In toxicity tests against human fibroblasts, several compounds showed low toxicity. One compound, 5c (riluzole; 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine), a known drug approved for CNS pathologies, was active in combination and is suitable for early preclinical evaluation of its potential for label extension as a PTR1 inhibitor and antiparasitic drug candidate.
 ...
PMID:Virtual screening identification of nonfolate compounds, including a CNS drug, as antiparasitic agents inhibiting pteridine reductase. 2112 22

A chemical database of 30 representative imidazo-azines was built and screened against important tropical disease targets by computational docking. After three rounds of screening, an interaction profile was generated and analyzed. On the basis of binding energy and ligand efficiency, it was concluded that in general, imidazo-azine scaffold has a potential of being selective and simultaneous inhibitor against the five receptors Pf-dihydrofolate reductase, Pf-enoyl acyl carrier protein reductase, Pf-protein kinase 7, Mt-pantothenate synthetase and Mt-thymidine monophosphate kinase. Interestingly, two compounds 2-(4-chlorophenyl)-N-cyclohexyl-6-methylH-imidazo[1,2-a]pyridine-3-amine (MCL011) and N-cyclohexyl-2-(4-methoxyphenyl)-6-methylH-imidazo[1,2-a]pyridine-3-amine (MCL017) showed highest binding energy against four targets namely Pf-dihydrofolate reductase, Pf-enoyl acyl carrier protein reductase, Pf-protein kinase 7 and Mt-pantothenate synthetase. Eventually, in order to improve the decision making and success rate in actual efficacy evaluations other criteria such as lead-likeness were envisaged.
 ...
PMID:In silico investigation of medicinal spectrum of imidazo-azines from the perspective of multitarget screening against malaria, tuberculosis and Chagas disease. 2466 69

A series of antifolate compounds, i.e. 1-(4-chlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine, or cycloguanil analogues, have shown effective inhibiting properties against Plasmodium falciparum dihydrofolate reductase (PfDHFR). In this work, the stereoselectivity of PfDHFR to the R and S enantiomer of cycloguanil analogues was obtained from molecular docking calculations and integrated into QSAR study to obtain a more accurate prediction model. Results indicate that PfDHFR can bind to cycloguanil analogues in the R and S enantiomers. Cycloguanil analogues with alkyl chain substituent prefer the R enantiomer over S because they do not experience steric hindrance with the Phe58 side chain, while cycloguanil analogues with phenol chain substituent prefer the S enantiomer over R because they do not experience steric hindrance with Leu46 and Met55 side chains. Particle swarm optimization and support vector regression were used to select relevant descriptors and generate the effective prediction model, with a high statistical significance level (r2training = 0.941; r2test = 0.884).
 ...
PMID:Application of molecular docking and PSO-SVR intelligent approaches in antimalarial activity prediction of enantiomeric cycloguanil analogues. 3038 63