Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel h LDHA Inhibitors.

A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A ( h LDHA) 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(1 H )-ones 22/23 ( a - c ) and 4-aryl-2-chloropyrimidines ( 1 - 4 ). The inhibitory activity against h LDHA of the synthesized hybrids was evaluated, resulting IC 50 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 IC 50 values (<20 μM) and developed a preliminary SAR.