Title:Novel Dipeptides Bearing Sulfonamide as Antimalarial and Antitrypanosomal
Agents: Synthesis and Molecular Docking
Volume: 18
Issue: 3
Author(s): Ogechi Chinelo Ekoh*, Uchechukwu Okoro, David Ugwu, Rafat Ali, Sunday Okafor, Daniel Ugwuja and Solomon Attah
Affiliation:
- Department of Industrial Chemistry, Evangel University, Akaeze, Ebonyi State, Nigeria
- Department of Chemistry, Indian Institute of Technology,
Kanpur, India
Keywords:
Sulphonamide, dipeptide, antimalarial, antitrypanosomal, glycine, molecular docking.
Abstract: Objective: 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.
Background: 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.
Methods: 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, 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.
Conclusion: 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.
