Design, Synthesis And Structure-activity Relationship Study Of Trypanosoma Brucei Leucyl-tRNA Synthetase Inhibitors

Human African Trypanosomiasis(HAT), also known as sleeping sickness, is a parasitic disease caused by protozoa Trypanosoma brucei(T. brucei) which is transmitted to human by infected tsetse flies. Leucyl-t RNA synthetase(LeuRS) is a reasonable drug target, and it has been successfully used for the development of antibacterial drugs. Our group found it a potentially promising research direction for LeuRS inhibitors to be candidates of antitrypanosomal agents. Through virtual screening and biological assays, we found two types of scaffolds, 3-pyrrolinone and N-(4-sulfamoylphenyl)thiourea which showed moderate T. brucei Leu RS(TbLeuRS) inhibitory activity, and derived the N-(4-sulfamoylphenyl)thiourea scaffold. This paper focuses on the design, synthesis, biological assays and structure-activity relationship study of the latter two scaffolds.To optimize the TbLeuRS inhibitory activity of lead compound 1(IC50 = 77.1 ?M) in N-(4-sulfamoylphenyl)thiourea scaffold, 17 compounds were designed and synthesized with substitutions of sulfamoyl and thiourea moieties based on the structural characteristics of the native Leu RS substrate. Biological evaluation showed that the most potent compound was compound 30(IC50 = 26.1 ?M), with 3-fold improvement in TbLeuRS inhibitory activity compared to compound 1.For N-sulfamoylphenylamide derivatives, N-(4-sulfamoylphenyl)amide and N-(3-sulfamoylphenyl)amide compounds were designed and synthesized. The most potent compounds in 1,4- and 1,3-substituted were compound 79(IC50 = 31.3 ?M) and compound 106(IC50 = 0.7 ?M), respectively. Compound 106 showed more than 100-fold improvement in TbLeuRS inhibition compared to the lead compound 1.In summary, 53 comopunds, with the structure of N-(4-sulfamoylphenyl)thiourea and N-sulfamoylphenylamide, have been designed and synthesized, and structure-activity relationship have been summarized. N-(3-sulfamoylphenyl)amide derivatives have been found as potent inhibitors against TbLeuRS, which provide guidance for the future structural design and discovery of antitrypanosomal agents.