16462-27-4Relevant articles and documents
Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation
Chen, Wenhua,Yao, Xue,Huang, Zhenghui,Mao, Fei,Guan, Longfei,Tang, Yun,Jiang, Hualiang,Li, Jian,Huang, Jin,Jiang, Lubin,Zhu, Jin
supporting information, p. 250 - 254 (2018/04/05)
Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme (IC50 = 6.8 ± 1.8 μmol/L and IC50 = 8.8 ± 0.3 μmol/L) and P. falciparum 3D7 strain (IC50 = 2.9 μmol/L). Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P. falciparum Dd2 strain (IC50 = 1.1 μmol/L) than pyrimethamine (IC50 > 10 μmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9 (IC50 = 2.6 μmol/L) and GB4 (IC50 = 1.0 μmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.
N-(4-substituted phenethyl) acetamide compounds and use thereof
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Paragraph 0048; 0058-0059, (2017/09/01)
The invention relates to acetamide compounds and a use thereof, and discloses N-(4-substituted phenethyl) acetamide compounds with a novel structure. A result of in-vitro activity test experiments shows that the compounds have inhibitory activity against
Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens
Bag, Seema,Tawari, Nilesh R.,Degani, Mariam S.,Queener, Sherry F.
experimental part, p. 3187 - 3197 (2010/07/08)
The present work deals with design, synthesis and biological evaluation of novel, diverse compounds as potential inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms; Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium (ma). A set of 14 structurally diverse compounds were designed with varying key pharmacophoric features of DHFR inhibitors, bulky distal substitutions and different bridges joining the distal part and 2,4-diaminopyrimidine nucleus. The designed compounds were synthesized and evaluated in enzyme assay against pc, tg and ma DHFR. The rat liver (rl) DHFR was used as mammalian standard. As the next logical step of the project, flexible molecular docking studies were carried out to predict the binding modes of these compounds in pcDHFR active site and the obtained docked poses were post processed using MM-GBSA protocol for prediction of relative binding affinity. The predicted binding modes were able to rationalize the experimental results in most cases. Of particular interest, both the docking scores and MM-GBSA predicted ΔGbind were able to distinguish between the active and low active compounds. Furthermore, good correlation coefficient of 0.797 was obtained between the IC50 values and MM-GBSA predicted ΔGbind. Taken together, the current work provides not only a novel scaffold for further optimization of DHFR inhibitors but also an understanding of the specific interactions of inhibitors with DHFR and structural modifications that improve selectivity.
