期刊
PHARMACEUTICALS
卷 15, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/ph15070792
关键词
hLDHA inhibitors; quinolones; pyrimidines; fragment-based drug design; docking
资金
- Spanish Ministerio de Ciencia, Innovacion, y Universidades [RTI2018-098560-B-C22]
- FEDER funds of the European Union
- Universidad de Jaen, Vicerrectorado de Investigacion, PAIUJA
- Consejeria de Innovacion, Ciencia y Empresa (Junta de Andalucia, Spain)
A series of novel pyrimidine-quinolone hybrids were designed and synthesized as inhibitors of lactate dehydrogenase A (hLDHA) using a computer-aided approach. By evaluating the inhibitory activity of different synthesized hybrids, new compounds with promising activity were successfully designed, and a preliminary structure-activity relationship was established.
A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (hLDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (10-21 and 24-31) were studied in silico, and those with the 2-aminophenylsulfide (U-shaped) and 4-aminophenylsulfide linkers (24-31) were finally selected. These new pyrimidine-quinolone hybrids (24-31)(a-c) were easily synthesized in good to excellent yields by a green catalyst-free microwave-assisted aromatic nucleophilic substitution reaction between 3-(((2/4-aminophenyl)thio)methyl)quinolin-2(1H)-ones 22/23(a-c) and 4-aryl-2-chloropyrimidines (1-4). The inhibitory activity against hLDHA of the synthesized hybrids was evaluated, resulting IC50 values of the U-shaped hybrids 24-27(a-c) much better than the ones of the 1,4-linked hybrids 28-31(a-c). From these results, a preliminary structure-activity relationship (SAR) was established, which enabled the design of novel 1,3-linked pyrimidine-quinolone hybrids (33-36)(a-c). Compounds 35(a-c), the most promising ones, were synthesized and evaluated, fitting the experimental results with the predictions from docking analysis. In this way, we obtained novel pyrimidine-quinolone hybrids (25a, 25b, and 35a) with good IC50 values (<20 mu M) and developed a preliminary SAR.
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