Lead optimization of selective tubulin inhibitors as anti-trypanosomal agents. 2019

Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.

Previously synthesized tubulin inhibitors showed promising in vitro selectivity and activity against Human African Trypanosomiasis. Current aim is to improve the ligand efficiency and reduce overall hydrophobicity of the compounds, by lead optimization. Via combinatorial chemistry, 60 new analogs were synthesized. For biological assay Trypanosoma brucei brucei Lister 427 cell line were used as the parasite model and for the host model human embryonic kidney cell line HEK-293 and mouse macrophage cell line RAW 264.7 were used to test efficacy. Of the newly synthesized compounds 5, 39, 40, and 57 exhibited IC50s below 5 µM inhibiting the growth of trypanosome cells and not harming the mammalian cells at equipotent concentration. Comparably, the newly synthesized compounds have a reduced amount of aromatic moieties resulting in a decrease in molecular weight. Due to importance of tubulin polymerization during protozoan life cycle its activity was assessed by western blot analyses. Our results indicated that compound 5 had a profound effect on tubulin function. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.

UI MeSH Term Description Entries
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067996 RAW 264.7 Cells A transformed macrophage cell line isolated from ASCITES of mice infected with ABELSON MURINE LEUKEMIA VIRUS. RAW 264.7 Cell Line,264.7 Cell, RAW,264.7 Cells, RAW,Cell, RAW 264.7,Cells, RAW 264.7,RAW 264.7 Cell
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014344 Trypanocidal Agents Agents destructive to the protozoal organisms belonging to the suborder TRYPANOSOMATINA. Trypanocidal Drugs,Trypanocides,Trypanosomicidal Agents,Trypanosomicides,Agents, Trypanocidal,Agents, Trypanosomicidal,Drugs, Trypanocidal
D014346 Trypanosoma brucei brucei A hemoflagellate subspecies of parasitic protozoa that causes nagana in domestic and game animals in Africa. It apparently does not infect humans. It is transmitted by bites of tsetse flies (Glossina). Trypanosoma brucei,Trypanosoma brucei bruceus,Trypanosoma bruceus,brucei brucei, Trypanosoma,brucei, Trypanosoma brucei,bruceus, Trypanosoma,bruceus, Trypanosoma brucei
D014353 Trypanosomiasis, African A disease endemic among people and animals in Central Africa. It is caused by various species of trypanosomes, particularly T. gambiense and T. rhodesiense. Its second host is the TSETSE FLY. Involvement of the central nervous system produces "African sleeping sickness." Nagana is a rapidly fatal trypanosomiasis of horses and other animals. African Sleeping Sickness,Nagana,African Trypanosomiasis,African Sleeping Sicknesses,African Trypanosomiases,Sickness, African Sleeping,Sicknesses, African Sleeping,Sleeping Sickness, African,Sleeping Sicknesses, African,Trypanosomiases, African
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D050257 Tubulin Modulators Agents that interact with TUBULIN to inhibit or promote polymerization of MICROTUBULES. Microtubule Modulator,Tubulin Inhibitor,Tubulin Modulator,Tubulin Polymerization Inhibitor,Tubulin Polymerization Promoter,Tubulin Promoter,Microtubule Modulators,Tubulin Inhibitors,Tubulin Polymerization Inhibitors,Tubulin Polymerization Promoters,Tubulin Promoters,Inhibitor, Tubulin,Inhibitor, Tubulin Polymerization,Inhibitors, Tubulin,Inhibitors, Tubulin Polymerization,Modulator, Microtubule,Modulator, Tubulin,Modulators, Microtubule,Modulators, Tubulin,Polymerization Inhibitor, Tubulin,Polymerization Inhibitors, Tubulin,Polymerization Promoter, Tubulin,Polymerization Promoters, Tubulin,Promoter, Tubulin,Promoter, Tubulin Polymerization,Promoters, Tubulin,Promoters, Tubulin Polymerization
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055808 Drug Discovery The process of finding chemicals for potential therapeutic use. Drug Prospecting,Discovery, Drug,Prospecting, Drug

Related Publications

Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
September 2012, Bioorganic & medicinal chemistry letters,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
May 2022, Bioorganic & medicinal chemistry,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
June 2014, European journal of medicinal chemistry,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
September 1999, Expert opinion on investigational drugs,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
December 2020, Bioorganic & medicinal chemistry,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
February 2004, Bioorganic & medicinal chemistry,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
November 2006, European journal of medicinal chemistry,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
January 2015, Bioorganic & medicinal chemistry letters,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
August 2009, Bioorganic & medicinal chemistry,
Anran Zhao, and Yaxin Li, and Cody M Orahoske, and Brittny Schnur, and Abboud Sabbagh, and Wenjing Zhang, and Bibo Li, and Bin Su
March 2008, Biological & pharmaceutical bulletin,
Copied contents to your clipboard!