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. Enan...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Shiraz University of Medical Sciences
2023-09-01
|
| Series: | Trends in Pharmaceutical Sciences |
| Subjects: | |
| Online Access: | https://tips.sums.ac.ir/article_49566_9cdc6d805c4acda90110e5d6dd39466f.pdf |
| _version_ | 1797562205553557504 |
|---|---|
| author | Hossein Sadeghpour Ramin Miri Seyed Ahmad Ebadi Shima Mohammadebrahimi Elham Riazimontazer |
| author_facet | Hossein Sadeghpour Ramin Miri Seyed Ahmad Ebadi Shima Mohammadebrahimi Elham Riazimontazer |
| author_sort | Hossein Sadeghpour |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T18:25:01Z |
| format | Article |
| id | doaj.art-bbbd0bb59ccf4259a02660d129dec5fa |
| institution | Directory Open Access Journal |
| issn | 2423-5652 |
| language | English |
| last_indexed | 2024-03-10T18:25:01Z |
| publishDate | 2023-09-01 |
| publisher | Shiraz University of Medical Sciences |
| record_format | Article |
| series | Trends in Pharmaceutical Sciences |
| spelling | doaj.art-bbbd0bb59ccf4259a02660d129dec5fa2023-11-20T07:05:57ZengShiraz University of Medical SciencesTrends in Pharmaceutical Sciences2423-56522023-09-019319120210.30476/tips.2023.98380.118749566Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5Hossein Sadeghpour0Ramin Miri1Seyed Ahmad Ebadi2Shima Mohammadebrahimi3Elham Riazimontazer4Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.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.https://tips.sums.ac.ir/article_49566_9cdc6d805c4acda90110e5d6dd39466f.pdf34-dihydropyrimidine-2-onebiginelli reactionkinesin motor proteindocking |
| spellingShingle | Hossein Sadeghpour Ramin Miri Seyed Ahmad Ebadi Shima Mohammadebrahimi Elham Riazimontazer Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5 Trends in Pharmaceutical Sciences 3 4-dihydropyrimidine-2-one biginelli reaction kinesin motor protein docking |
| title | Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5 |
| title_full | Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5 |
| title_fullStr | Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5 |
| title_full_unstemmed | Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5 |
| title_short | Design, synthesis and docking study of 3,4-dihydropyrimidine-2-one derivatives as inhibitors of the Mitotic Kinesin, Eg5 |
| title_sort | design synthesis and docking study of 3 4 dihydropyrimidine 2 one derivatives as inhibitors of the mitotic kinesin eg5 |
| topic | 3 4-dihydropyrimidine-2-one biginelli reaction kinesin motor protein docking |
| url | https://tips.sums.ac.ir/article_49566_9cdc6d805c4acda90110e5d6dd39466f.pdf |
| work_keys_str_mv | AT hosseinsadeghpour designsynthesisanddockingstudyof34dihydropyrimidine2onederivativesasinhibitorsofthemitotickinesineg5 AT raminmiri designsynthesisanddockingstudyof34dihydropyrimidine2onederivativesasinhibitorsofthemitotickinesineg5 AT seyedahmadebadi designsynthesisanddockingstudyof34dihydropyrimidine2onederivativesasinhibitorsofthemitotickinesineg5 AT shimamohammadebrahimi designsynthesisanddockingstudyof34dihydropyrimidine2onederivativesasinhibitorsofthemitotickinesineg5 AT elhamriazimontazer designsynthesisanddockingstudyof34dihydropyrimidine2onederivativesasinhibitorsofthemitotickinesineg5 |