Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5

A series of 3,4-dihydropyrimidine-2-one derivatives were designed and synthesized as monastrol analogs by Biginelli cyclocondensation of a β-keto compounds and aromatic aldehyde with urea or thiourea. Biginelli cyclocondensation usually produces racemic mixtures of 3,4-dihydropyrimidine-2-ones. Enantiomers of 3,4-dihydropyrimidine-2-ones (R and S) often show different biological activities and may even have an opposite action profile. Therefore, developing of the stereoselective synthesis of 3,4-dihydropyrimidine-2-ones is one of the priorities of medicinal chemistry. Following observed diverse pharmacological effects of monastrol, 3,4-dihydropyrimidine-2-ones as new anti-cancer agents are the pharmacological category which improve and decrease the side effects of dihydropyrimidines especially resistance to chemotherapeutic drugs. 3,4-Dihydropyrimidine-2-ones followed their anticancer effects by inhibiting the kinesin motor protein. Because of the specific function of these proteins in mitosis, targeting the Kinesin spindle protein (KSP, or Eg5) as the most dramatic target of the mitotic kinesin family open up an opportunity for the progress of more selective antimitotics with an improved side effect profile. These facts prompted us to investigate if the effects of inhibitory enantiomers (R and S) of 3,4-dihydropyrimidine-2-ones could possibly differ from each other. Therefore, molecular docking of both R and S stereoisomers of 3,4-dihydropyrimidine-2-ones and monastrol was performed to study the interaction between inhibitors and the kinesin spindle protein binding site. According to docking studies, S stereoisomer of D2 (SD2) has the best score among the synthesized compounds and shows probably more stable binding with the active site of the enzyme and can be considered as a candidate for biological evaluation.