Synthesis and biological evaluation of Val–Val dipeptide–sulfonamide conjugates

• Published in: Archiv der Pharmazie (Weinheim) 2020-07, Vol.353 (7), p.e2000074-n/a
• Main Authors: Ezugwu, James A., Okoro, Uchechukwu C., Ezeokonkwo, Mercy A., Bhimapaka, Chinaraju, Okafor, Sunday N., Ugwu, David I., Ugwuja, Daniel I.
• Format: Article
• Language: English
• Subjects: Antibiotics; antimalarial; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; antioxidant; benzenesulfonamide; Dipeptides - chemistry; Dipeptides - pharmacology; Dose-Response Relationship, Drug; drug resistance; Fourier transforms; in silico studies; Ions; Molecular Structure; NMR; Nuclear magnetic resonance; Oxidative Stress - drug effects; Parasitic Sensitivity Tests; Plasmodium falciparum - drug effects; Structure-Activity Relationship; Sulfanilamide - chemistry; Sulfanilamide - pharmacology; Val–Val dipeptide
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202000074

Novel Val–Val dipeptide–benzenesulfonamide conjugates were reported in this study. These were achieved by a condensation reaction of p‐substituted benzenesulfonamoyl alkanamides with 2‐amino‐4‐methyl‐N‐substituted phenyl butanamide using classical peptide‐coupling reagents. The compounds were characterized using Fourier transform infrared, 1H‐nuclear magnetic resonance (NMR), 13C‐NMR, and electrospray ionization–high‐resolution mass spectrometry spectroscopic techniques. As predicted from in silico studies, the Val–Val dipeptide–benzenesulfonamide conjugates exhibited antimalarial and antioxidant properties that were analogous to the standard drug. The synthesized compounds were evaluated for in vivo antimalarial activity against Plasmodium berghei. The hematological analysis was also conducted on the synthesized compounds. At 50 mg/kg body weight, compounds 8a, 8d, and 8g–i inhibited the multiplication of the parasite by 48–54% on Day 7 of posttreatment exposure, compared with the 67% reduction with artemisinin. All the synthesized dipeptides had a good antioxidant property, but it was less when compared with vitamin C. The dipeptides reported herein showed the ability to reduce oxidative stress arising from the malaria parasite. Novel Val–Val dipeptide–benzenesulfonamide conjugates were synthesized and studied for their antimalarial activity. As predicted from in silico studies, the conjugates exhibited antimalarial and antioxidant properties that were analogous to the standard drug. Compounds 8a, 8d, and 8g–i inhibited the multiplication of the parasite Plasmodium berghei by 48–54% on Day 7 of exposure, compared with the 67% reduction with artemisinin.