Uchechukwu Chris Okoro

Four novel glycine-tyrosine dipeptide sulphonamide deriavtives were synthesized, characterized via 1HNMR, 13CNMR, FTIR and HRMS spectroscopic techniques and their anti-alzheimer’s, antioxidant activities were investigated. The base promoted reaction of substituted benzenesulphonyl chloride with L-glycine gave compound (7a-7b) in excellent yields. Compounds (12a-12d) were achieved by amidation of substituted benzenesulphonamoyl derivatives with alkanamides (11) in the presence of EDC.HCl and HOBt as peptide coupling reagents. The antimicrobial properties were determined by agar dilution method and the antioxidant properties were also investigated. The anti-alzheimer’s study revealed that the IC50 value of compound 12c showed a significant inhibition of 0.65 mg/mL comparable with the IC50 value of galantamine (0.70 mg/mL). In the antioxidant study, IC50 value of compound 12b (0.76 mg/mL) is comparatively almost the same with that of vitamin C (0.79 mg/mL). This implies that compound 12b can be serve as a lead potent antioxidant agent.

The choice of design and synthesis of new dipeptide derivatives is due to their broad pharmacological activities against various diseases. In present study, eight novel dipeptides incorporating sulphonamide functionality (8a-h) were synthesised via the reaction of benzenesulphonyl chloride and L-proline to afford benzenesulphonamides. The condensation reaction of benzenesulphonamides and carboxamide derivatives, using peptide coupling reagents afforded the dipeptide compounds (8a-h). The structural validation of the compounds was done using IR, 1H NMR, 13C NMR and MS spectrometry. Molecular docking studies revealed favourable interactions between the compounds and key amino acid residues in the active site of the protein targets. The drug-likeness study showed that the compounds comply with Lipinski’s rule of five, indicating strong potential as orally bioavailable candidates. Compound 8a exhibited superior antidiabetic activity compared to the standard clinical drug, acarbose. Antioxidant screening demonstrated that compound 8g, with an IC50 value of 0.214 µg/mL, exhibited comparable activity to ascorbic acid (IC50: 0.213 µg/mL). In the carrageenan-induced rat paw edema bioassay, at 0.5 h, compounds 8a-h showed strong anti-inflammatory inhibition with percentage inhibition in the range of 97.67-86.64 %, compared to the reference drug, indomethacin (75.55 %). Some of the dipeptide derivatives are identified as promising therapeutic agents for further studies.

The development of Sulphonamides is a fascinating and informative area in medicinal chemistry, its functional group has a long and rich history in organic chemistry and drug discovery. The objective of this work is to synthesize and characterize 4-methylbenzenesulphonamides derivatives using 4-methylbenzenesulphonyl chlorides and amino acids (leucine, histidine, phenylalanine, and cysteine) as precursors, then, biological studies were carried out. The FTIR spectroscopic results confirm characteristic functional group, p-disubstituted benzene, -SO₂-NH₂, R₃N, C=O, R₂NH, Amide C=O, the ^IH-NMR spectrum, the peaks confirm 2^o amine, p- disubstituted benzene), m- disubstituted benzene), CH₃-n and CH₃-CO and the ¹³CNMR, (acetyl C=O), (C-S=O), amide C=O, (C-H), acetyl CH₃, -CH₃, aromatic carbons); the results of the in silico antibacterial studies disclosed that the range of the affinity of binding is between -6.3 to -8.7 kcal/mol, with the ligands interacting more positively than other investigated microbes with the staphylococcus variant's 6xg5 receptor, while the results of the in vitro antibacterials studies showed that at 200 mg/mL, the test organisms exhibit a zone of clearance or inhibition that varies in size from 0 to 28 mm. The spectroscopic results support the proposed structures of the compounds, the synthesized compounds have significant antibacterial potency in the respective bacteria cells, as demonstrated by the in silico antibacterial studies; these findings suggest that the synthesized compounds could be used as future antibacterial agents. According to the in vitro antimicrobial investigation, the majority of the produced compounds had antibacterial properties.

The synthesis of new functionalized linear diaza and triaza phenothiazine and phenoxazines and their in silico and in vitro anti-Alzheimer activity is reported. Fifteen new amide derivatives (8-11 & 13-24) were synthesized by the reactions of phenothiazines/phenoxazine (6 or 12) and various aliphatic and aromatic primary amides (7) in the presence of nickel catalyst and anhydrous potassium carbonate under nitrogen atmosphere. The FTIR, 1H NMR, 13C NMR and HR-MS spectra of the synthesized compounds were in agreement with the assigned structures. All the 15 new derivatives were screened for their in silico and in vitro anti-Alzheimer’s activity using the inhibition of acetylcholinesterase and butyrylcholinesterase. The results of the in silico experiment showed that most of the synthesized derivatives had good binding energies, binding interaction and bond distances. The most active derivatives in the in silico studies was compounds 18 (-12.5 and -11.5 kcal/mol) against acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 18 had the best in vitro inhibitory activity against acetylcholinesterase and butyrylcholinesterase (99.37% and 82.35%). The results of in silico experiment were greatly in agreement with the results of in vitro studies. The structure-activity relationship studies revealed that the phenothiazine derivatives had better in silico and in vitro activities. Furthermore, 2-substitutted phenothiazines had better activity than the unsubstituted phenothiazines. The synthesized compounds showed promising in silico and in vitro activities against acetylcholinesterase and butyrylcholinesterase and as such could be further developed for the treatment of Alzheimer’s disease.

A new series of novel dipeptide sulfonamide analogues were designed, synthesized, and screened for their in silico studies and in vivo antimalarial activities. The synthesized compounds (50 mg/Kg) showed significant activity against P. berghei (NK65) with % inhibition values in (5.9 to 64.7 %) range in when compared with reference drug, artemisinin (66.7 %) in a four day suppressive assay. The in silico studies predicted favorable binding affinity of compounds with target protein residues with high dock score against P. falciparum falcipain 2 (FP‐2) and falcipain 3 (FP‐3) proteins in comparison with the reference ligands. The synthesized compounds showed druggable properties, and the predicted (absorption, distribution, metabolism, excretion and toxicities (ADMET) properties were within the acceptable limits. Molecular dynamics simulation study of the most active compound, 8 e was performed in order to further validate the stability of the protein‐ligand complex and the protein‐ligand interactions.

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.