- Structure elaboration of isoniazid: synthesis, in silico molecular docking and antimycobacterial activity of isoniazid–pyrimidine conjugates
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Abstract: Designing small molecule-based new drug candidates through structure modulation of the existing drugs has drawn considerable attention in view of inevitable emergence of resistance. A new series of isoniazid–pyrimidine conjugates were synthesize
- Kaur, Hardeep,Singh, Lovepreet,Chibale, Kelly,Singh, Kamaljit
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p. 949 - 955
(2019/11/14)
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- Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents
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In an attempt to explore novel and more potent antileishmanial compounds to diversify the current inhibitors, we pursued a medicinal chemistry-driven strategy to synthesize novel scaffolds with common pharmacophoric features of dihydropyrimidine and chalcone as current investigational antileishmanial compounds. Based on the reported X-ray structure of Pteridine reductase 1 (PTR1) from Leishmania major, we have designed a number of dihydropyrimidine-based derivatives to make specific interactions in PTR1 active site. Our lead compound 8i has shown potent in vitro antileishmanial activity against promastigotes of L. Major and Leishmania donovani with IC50 value of 0.47 1/4g/ml and 1.5 1/4g/ml respectively. The excellent in vitro activity conclusively revealed that our lead compound is efficient enough to eradicate both visceral and topical leishmaniasis. In addition, docking analysis and in silico ADMET predictions were also carried out. Predicted molecular properties supported our experimental analysis that these compounds have potential to eradicate both visceral and topical leishmaniasis.
- Rashid, Umer,Sultana, Riffat,Shaheen, Nargis,Hassan, Syed Fahad,Yaqoob, Farhana,Ahmad, Muhammad Jawad,Iftikhar, Fatima,Sultana, Nighat,Asghar, Saba,Yasinzai, Masoom,Ansari, Farzana Latif,Qureshi, Naveeda Akhter
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p. 230 - 244
(2016/04/05)
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- Primaquine-pyrimidine hybrids: Synthesis and dual-stage antiplasmodial activity
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Abstract A series of novel pyrimidine-primaquine hybrids were synthesized and their effectiveness against the blood and liver stages of malaria parasites was evaluated. The hybrids displayed enhanced liver stage in vitro activity against P. berghei liver
- Kaur, Hardeep,Machado, Marta,De Kock, Carmen,Smith, Peter,Chibale, Kelly,Prudêncio, Miguel,Singh, Kamaljit
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p. 266 - 273
(2015/07/08)
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- Antagonism of L-type Ca2+ channels CaV1.3 and Ca V1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics
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The L-type calcium channel (LTCC) CaV1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through CaV1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a Ca V1.3 antagonist selective over CaV1.2 is essential because CaV1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of CaV1.3 relative to CaV1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of CaV1.3 and CaV1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for CaV1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for CaV1.3 over CaV1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in CaV1.3 and Ca V1.2 LTCCs are very similar.
- Kang, Soosung,Cooper, Garry,Dunne, Sara Fernandez,Luan, Chi-Hao,James Surmeier,Silverman, Richard B.
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p. 4365 - 4373
(2013/07/25)
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- Synthesis of enantiomerically pure 4-aryl-3,4-dihydropyrimidin-2(1H)-ones via enzymatic resolution: preparation of the antihypertensive agent (R)-SQ 32926
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A practical and short synthesis of the enantiomerically pure dihydropyrimidone antihypertensive agent (R)-SQ 32926 has been developed. The key step in the synthesis is the enzymatic resolution of an N3-acetoxymethyl-activated dihydropyrimidone precursor b
- Schnell, Barbara,Strauss, Ulrike T.,Verdino, Petra,Faber, Kurt,Kappe, C. Oliver
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p. 1449 - 1453
(2007/10/03)
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- Microwave-assisted high-speed parallel synthesis of 4-aryl-3,4- dihydropyrimidin-2(1H)-ones using a solventless biginelli condensation protocol
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4-Aryl-3,4-dihydropyrimidin-2-(1H)-ones 4a-o are synthesized by a microwave-promoted, solvent-free modification of the Biginelli three- component cyclocondensation reaction. The novel method employs neat mixtures of β-ketoesters, aryl aldehydes, and urea
- Kappe, C. Oliver,Kumar, Dalip,Varma, Rajender S.
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p. 1799 - 1803
(2007/10/03)
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