title: Synthesis and Biological Evaluation of Novel 8-Morpholinoimidazo[1,2-a]pyrazine Derivatives Bearing Phenylpyridine/Phenylpyrimidine-Carboxamides.
abstract: Herein we designed and synthesized three series of novel 8-morpholinoimidazo[1,2-a]pyrazine derivatives bearing phenylpyridine/phenylpyrimidine-carboxamides (compounds12a-g,13a-gand14a-g). All the compounds were evaluated for their IC50values against three cancer cell lines (A549, PC-3 and MCF-7). Most of the target compounds exhibited moderate cytotoxicity against the three cancer cell lines. Two selected compounds14b,14cwere further tested for their activity against PI3Kα kinase, and the results indicated that compound14cshowed inhibitory activity against PI3Kα kinase with an IC50value of 1.25 μM. Structure-activity relationships (SARs) and pharmacological results indicated that the replacement of the thiopyranopyrimidine with an imidazopyrazine was beneficial for the activity and the position of aryl group has a significant influence to the activity of these compounds. The compounds13a-gin which an aryl group substituted at the C-4 position of the pyridine ring were more active than12a-gsubstituted at the C-5 position. Moreover, the cytotoxicity of compounds14a-gbearing phenylpyrimidine-carboxamides was better than that of the compounds12a-g,13a-gbearing phenylpyridine-carboxamides. Furthermore, the substituents on the benzene ring also had a significant impact on the cytotoxicity and the pharmacological results showed that electron donating groups were beneficial to the cytotoxicity.
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. Shanxu9891@126.com.
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. sunchengyu0902@126.com.|Department of Pharmacy, The Affiliated Hospital of Chongqing Three Gorges Medical College, Chongqing 404000, China. sunchengyu0902@126.com.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. chen5950677@163.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. Zhengpw@126.com.
authors.forename: Pengwu
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Department of Pharmacy, The Affiliated Hospital of Chongqing Three Gorges Medical College, Chongqing 404000, China. zhouyong_0801@126.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy, The Affiliated Hospital of Chongqing Three Gorges Medical College, Chongqing 404000, China. 15223632072@163.com.
authors.forename: Hongying
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. zhuwufu-1122@163.com.
authors.forename: Wufu
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D011743:Pyrimidines; C030986:pyrimidine; C023666:pyridine
keywords: PI3Kα; imidazopyrazine; phenylpyridine-carboxamide; phenylpyrimidine-carboxamide; synthesis