Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094, Ukraine.
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine.
Mol Divers. 2022 Apr;26(2):993-1004. doi: 10.1007/s11030-021-10218-2. Epub 2021 Apr 2.
An implementation of the three-component one-pot approach to unsymmetrical 1,3,5-trisubstituted-1,2,4-triazoles into combinatorial chemistry is described. The procedure is based on the coupling of amidines with carboxylic acids and subsequent cyclization with hydrazines. After the preliminary assessment of the reagent scope, the method had 81% success rate in parallel synthesis. It was shown that over a billion-sized chemical space of readily accessible ("REAL") compounds may be generated based on the proposed methodology. Analysis of physicochemical parameters shows that the library contains significant fractions of both drug-like and "beyond-rule-of-five" members. More than 10 million of accessible compounds meet the strictest lead-likeness criteria. Additionally, 195 Mln of sp-enriched compounds can be produced. This makes the proposed approach a valuable tool in medicinal chemistry.
描述了一种将不对称 1,3,5-三取代-1,2,4-三唑的三组分一锅法转化为组合化学的方法。该方法基于脒与羧酸的偶联以及与肼的后续环化。在对试剂范围进行初步评估后，该方法在平行合成中的成功率为 81%。结果表明，基于所提出的方法可以生成数亿个易于获得的“REAL”化合物的化学空间。对物理化学参数的分析表明，该库包含大量具有类药性和“超越五规则”成员的化合物。超过 1000 万种可及化合物符合最严格的先导样标准。此外，可以生产 1.95 亿种富含 sp 的化合物。这使得所提出的方法成为药物化学中的一种有价值的工具。
