- Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation
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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.
- Chen, Wenhua,Yao, Xue,Huang, Zhenghui,Mao, Fei,Guan, Longfei,Tang, Yun,Jiang, Hualiang,Li, Jian,Huang, Jin,Jiang, Lubin,Zhu, Jin
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supporting information
p. 250 - 254
(2018/04/05)
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- Design and optimization of N-acylhydrazone pyrimidine derivatives as E. coli PDHc E1 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study
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By targeting the thiamin diphosphate (ThDP) binding site of Escherichia coli (E. coli) pyruvate dehydrogenase multienzyme complex E1 (PDHc E1), a series of novel ‘open-chain’ classes of ThDP analogs A, B, and C with N-acylhydrazone moieties was designed and synthesized to explore their activities against E. coli PHDc E1 in vitro and their inhibitory activity against microbial diseases were further evaluated in vivo. As a result, A1–23 exhibited moderate to potent inhibitory activities against E. coli PDHc E1 (IC50 = 0.15–23.55 μM). The potent inhibitors A13, A14, A15, C2, had strong inhibitory activities with IC50 values of 0.60, 0.15, 0.39 and 0.34 μM against E. coli PDHc E1 and with good enzyme-selective inhibition between microorganisms and mammals. Especially, the most powerful inhibitor A14 could 99.37% control Xanthimonas oryzae pv. Oryzae. Furthermore, the binding features of compound A14 within E. coli PDHc E1 were investigated to provide useful insights for the further construction of new inhibitor by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that A14 had most powerful inhibition against E. coli PDHc E1 due to the establishment of stronger interaction with Glu571, Met194, Glu522, Leu264 and Phe602 at active site of E.coli PDHc E1. It could be used as a lead compound for further optimization, and may have potential as a new microbicide.
- He, Haifeng,Xia, Hongying,Xia, Qin,Ren, Yanliang,He, Hongwu
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p. 5652 - 5661
(2017/10/09)
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- N-(4-substituted phenethyl) acetamide compounds and use thereof
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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
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Paragraph 0048; 0058-0059
(2017/09/01)
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- Structure aided design of chimeric antibiotics
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The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and
- Karoli, Tomislav,Mamidyala, Sreeman K.,Zuegg, Johannes,Fry, Scott R.,Tee, Ernest H.L.,Bradford, Tanya A.,Madala, Praveen K.,Huang, Johnny X.,Ramu, Soumya,Butler, Mark S.,Cooper, Matthew A.
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supporting information; experimental part
p. 2428 - 2433
(2012/05/19)
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- Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens
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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.
- Bag, Seema,Tawari, Nilesh R.,Degani, Mariam S.,Queener, Sherry F.
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experimental part
p. 3187 - 3197
(2010/07/08)
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- Folate-Synthesizing Enzyme System as Target for Development of Inhibitors and Inhibitor Combinations against Candida albicans - Synthesis and Biological Activity of New 2,4-Diaminopyrimidines and 4′-Substituted 4-Aminodiphenyl Sulfones
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The paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of DHFR and compared with their activity against DHFR derived from mycobacteria and Escherichia coli. To test for selectivity, also rat DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for inhibitory activity against SYN and the I50 values compared to those obtained previously against Plasmodium berghei- and E. coll-derived SYN. Surprisingly, QSAR equations show very similar structural dependencies. To find an explanation for the large difference in the I50 values observed for enzyme inhibition (SYN, DHFR) and for inhibition of cell cultures of Candida, mutant strains with overexpressed efflux pumps and strains in which such pumps are deleted were included in the study and the MICs compared. Efflux pumps were responsible for the low activity of some of the tested derivatives, others showed no increase in activity after pumps were knocked out. In this case it may be speculated that these derivatives are not able to enter the cells.
- Otzen, Thomas,Wempe, Ellen G.,Kunz, Brigitte,Bartels, Rainer,Lehwark-Yvetot, Gudrun,H?nsel, Wolfram,Schaper, Klaus-Jürgen,Seydel, Joachim K.
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p. 240 - 253
(2007/10/03)
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- A Convenient Synthesis of 2-Substituted 4-Amino-5-pyrimidinecarbonitriles
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Synthesis of the novel 2-halogenated 4-amino-5-pyrimidinecarbonitriles 3a,b starting from ethoxymethylenemalononitrile 1 and cyanamide is described.Nucleophilic substitution of the reactive halogen atom leads to the derivatives 5a-g,6 and 7a-h.
- Schmidt, Hans-Werner,Koitz, Gerald,Junek, Hans
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p. 1305 - 1307
(2007/10/02)
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- Organic synthetic methods benzylpyrimidine derivatives
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A method of preparation of 2,4-diamino-5-benzylpyrimidines involving the reaction of a 2,4-diamino-5-substituted methyl pyrimidine, for example 2,4-diamino-5-hydroxymethylpyrimidine, with an appropriately substituted phenol.
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