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

OBJECTIVE
Currently, there is a problem of ineffective chemotherapy to trypanosomiasis and the increasing emergence of malarial drug-resistant parasites. This research aimed to develop new dipeptide-sulfonamides as antiprotozoal agents.


BACKGROUND
Protozoan parasites cause severe diseases, with human African trypanosomaisis (HAT) and malaria leading 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.


METHODS
In order 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.


RESULTS
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. However, 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 haematological analysis and liver and kidney function tests showed that the new compounds had no adverse effect on the blood and organs.


CONCLUSIONS
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.