Journal of Medicinal Chemistry p. 6129 - 6152 (2010)
Update date:2022-08-03
Topics:
Coterón, Jose M.
Catterick, David
Castro, Julia
Chaparro, María J.
Díaz, Beatriz
Fernández, Esther
Ferrer, Santiago
Gamo, Francisco J.
Gordo, Mariola
Gut, Jiri
De Las Heras, Laura
Legac, Jennifer
Marco, Maria
Miguel, Juan
Mu?oz, Vicente
Porras, Esther
De La Rosa, Juan C.
Ruiz, Jose R.
Sandoval, Elena
Ventosa, Pilar
Rosenthal, Philip J.
Fiandor, Jose M.
Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2- cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
View MoreGuangzhou Chemical Reagent Factory
Contact:+86-20-8435 9820 or 8435 7345
Address:Southern Guangzhou, Guangdong, China
Contact:21-7631221 15884421033
Address:326 Science and technology,Shanghai,China
Xi'an caijing Opto-Electrical Science & Technology Co., LTD
Contact:+86-29-88294447
Address:NO.168 Zhangba Rd. East, Xi'an, P.R.China
website:http://www.enbridgepharm.com
Contact:+86-510-83591909
Address:Huishan Zone, Wuxi City, Jiangsu Province, P.R.China
Contact:86-25-84683399
Address:605, Phoenix Herui Plaza, No.389, South Taiping Road, Nanjing, China 210002
Doi:10.1080/00397910801914343
(2008)Doi:10.1021/jo0488917
(2004)Doi:10.1016/S0040-4020(00)01143-1
(2001)Doi:10.1021/ja01534a037
(1958)Doi:10.7164/antibiotics.51.210
(1998)Doi:10.1080/00397910008087346
(2000)