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 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.

Novel Leu-Val Based Dipeptide as Antimicrobial and Antimalarial Agents: Synthesis and Molecular Docking.

The increase of antimicrobial resistance (AMR) and antimalarial resistance are complex and severe health issues today, as many microbial strains have become resistant to market drugs. The choice for the synthesis of new dipeptide-carboxamide derivatives is as a result of their wide biological properties such as antimicrobial, anti-inflammatory, and antioxidant activities. The condensation reaction of substituted benzenesulphonamoyl pentanamides with the carboxamide derivatives using peptide coupling reagents gave targeted products (8a-j). The in silico antimalarial and antibacterial studies showed good interactions of the compounds with target protein residues and a higher dock score in comparison with standard drugs. In the in vivo study, compound 8j was the most potent antimalarial agent with 61.90% inhibition comparable with 67% inhibition for Artemisinin. In the in vitro antimicrobial activity, compounds 8a and 8b (MIC 1.2 × 10-3 M and 1.1 × 10-3 M) were most potent against S. aureus; compound 8a, 8b, and 8j with MIC 6.0 × 10-3 M, 5.7 × 10-4 M, and 6.5 × 10-4 M, respectively, were the most active against B. subtilis; compound 8b (MIC 9.5 × 10-4 M) was most active against E.coli while 8a, 8b and 8d were the most active against S. typhi. Compounds 8c and 8h (MIC 1.3 × 10-3 M) each were the most active against C. albicans, while compound 8b (MIC 1.3 × 10-4 M) was most active against A. niger.