Two series of new compounds with the general formula 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and their isosteric 2-imino derivatives were synthesized by the multicomponent reaction of the appropriate acetophenone, aromatic aldehyde, ammonium acetate, and malononitrile or ethyl cyanoacetate. The products were obtained with excellent yields. The prepared compounds were evaluated for their in vitro ability to inhibit p38 alpha-MAP kinase. Several compounds showed p38 MAP kinase inhibitory properties with IC(50) as low as 0.07 microM. This is the first time to report compounds with such scaffold as p38 alpha-MAP kinase inhibitors. This asserts the potentiality of multicomponent reactions in drug discovery.