Novel Dipeptides Bearing Sulfonamide as Antimalarial and Antitrypanosomal Agents: Synthesis and Molecular Docking

Currently, there is a problem of ineffective chemotherapy to trypanosomiasis and the increasing emergence of malaria drug-resistant parasites. The research aimed at the development of new dipeptide-sulfonamides as antiprotozoal agents.

Protozoan parasites cause severe diseases, with African human trypanosomiasis (HAT) and malaria standing on top of the list. The noted deficiencies of existing antitrypanosomal drugs and the worldwide resurgence of malaria, accompanied by the springing up of widespread drug-resistant protozoan parasites, represent a huge challenge in infectious disease treatment in tropical regions.

To discover new antiprotozoal agents, ten novel p-nitrobenzenesulphonamide derivatives incorporating dipeptide moiety were synthesized by the condensation reaction of 3-methyl-2-(4- nitrophenylsulphonamido)pentanoic acid (6) with substituted acetamides (4a-j) using peptide coupling reagents, characterized using 1H and 13C NMR, FTIR, HRMS and investigated for their antimalarial and antitrypanosomal activities in vivo employing standard methods.

At 100 mg/kg body weight, N-(2-(2,6-dimethylphenylamino)-2-oxoethyl)-3-methyl-2-(4- nitrophenylsulfonamido)pentanamide showed the highest activity by inhibiting P. berghei parasite by 79.89%, which was comparable with the standard drug (artemether-lumefantrine 79.77%). In the antitrypanosomal study, N-(2-(4-chlorophenylamino)-2-oxoethyl)-3-methyl-2-(4-nitrophenylsulfonamido) pentanamide, N-(2-(4-fluorophenylamino)-2-oxoethyl)-3-methyl-2-(4-nitrophenylsulfonamido) pentanamide and N-(2-(3-chlorophenylamino)-2-oxoethyl)-3-methyl-2-(4-nitrophenylsulfonamido) pentanamide were most potent in clearing Trypanosome brucei in mice, but they were less active than the standard drug (diminazene aceturate). Molecular docking results demonstrated good binding affinity among the reported derivatives and target proteins in the active place of the protein. The outcome of hematological analysis, liver, and kidney function tests showed that the new compounds had no adverse effect on the blood and organs.

The results of this research showed that the new compounds demonstrated interesting antitrypanosomal and antimalarial potentials. However, further research should be carried out on the synthesized derivatives as promising drug candidates for trypanosomiasis and malaria.