New chalcone derivatives as potential antimicrobial and antioxidant agent.

Seven chalcone derivatives were synthesized by the Claisen-Schmidt condensation. The structures of the compounds were confirmed by spectral data (Ultraviolet/visible, infrared, nuclear magnetic resonance and mass spectroscopy). The compounds were tested for their in silico and in vitro antimicrobial and antioxidant activities. The molecular docking assessments showed that all the compounds exhibited good binding affinity with the target microorganism proteins but, compounds 6e and 6g showed better binding affinity compared with the standards. The antimicrobial test revealed that all the compounds screened were active against Staphylococcus aureus and Bacillus subtilis and had minimum inhibitory concentrations (MIC) between 0.4 and 0.6 mg/mL. Compounds 6a, 6c and 6d had moderate activities on Salmonella typhi. Compounds 6b and 6c had moderate activity on Escherichia coli. Compound 6c had moderate activity on Aspergillus niger while compounds 6a and 6e had poor activity. All the compounds except compound 6e had no inhibition against Pseudomonas aeruginosa. The in-vitro antioxidant activity was assessed using ethylenediaminetetraacetate (EDTA) as the standard. Compounds 6c, 6e and 6g gave excellent inhibitory activity better than the standard. Compound 6a gave good activity at 500 µg/mL and 1000 µg/mL concentrations but, below the standard at 250 µg/mL and no inhibition at 125 µg/mL. Compound 6d had good inhibition at 500 µg/mL and 1000 µg/mL but, no inhibition at 125 µg/mL and 250 µg/mL. Compound 6b was found to be inactive in all the concentrations. Absorption, distribution, metabolism and excretion properties of the compounds were assessed using SwissADME. The results of lead likeness showed that compound 6e is a lead-like molecule.

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.

Synthesis and biological evaluation of Val-Val dipeptide-sulfonamide conjugates.

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, 1 H-nuclear magnetic resonance (NMR), 13 C-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 Phenoxazinones as potent agonist of PPAR-α: design, synthesis, molecular docking and in vivo studies.

BACKGROUND: The use of statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for the treatment of dyslipidemia has been associated with dose limiting hepatoxicity, mytotoxicity and tolerability due to myalgias thereby necessitating the synthesis of new drug candidates for the treatment of lipid disorder. METHODS: The reaction of appropriate benzenesulphonamide with substituted phenoxazinone in the presence of phenylboronic acid gave the targeted compounds. The molecular docking study were carried out using autodock tool against peroxisome proliferator activated receptor alpha. The in vivo lipid profile were assayed using conventional methods. The kidney and liver function test were carried out to assess the effect of the derivatives on the organs. The LD50 of the most active derivatives were determined using mice. RESULTS: The targeted compounds were successfully synthesized in excellent yields and characterized using spectroscopic techniques. The results of the molecular docking experiment showed that they were good stimulant of peroxisome proliferator activated receptor alpha. Compound 9f showed activity at Ki of 2.8 nM and binding energy of 12.6 kcal/mol. All the compounds tested reduced triglyceride, total cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol level in the mice model. Some of the reported compounds also increased high density lipoprotein cholesterol level in the mice. The compounds did not have appreciable effect on the kidney and liver of the mice used. The LD50 showed that the novel compounds have improved toxicity profile. CONCLUSION: The synthesis of fifteen new derivatives of carboxamides bearing phenoxazinone and sulphonamide were successful. The compounds possessed comparable activity to gemfibrozil. The reported compounds had better toxicity profile than gemfibrozil and could serve as a replacement for the statins and fibrate class of lipid agents.

Synthesis of proline derived benzenesulfonamides: A potent anti-Trypanosoma brucei gambiense agent.

Thousands of death in Africa and other developing nations are still attributed to trypanosomiasis. Excessive sleep has been associated with increased inflammation. We report herein, the synthesis, antitrypanosomal and anti-inflammatory activities of eight new carboxamide derivatives bearing substituted benzenesulfonamides. The base promoted reactions of l-proline and L-4-hydroxyproline with substituted benzenesulfonyl chlorides gave the benzenesulfonamides (11a-h) in excellent yields. Boric acid mediated amidation of the benzenesulfonamides (11a-h) and p-aminobenzoic acid (12) gave the new carboxamides (13a-h) in excellent yields. The new carboxamides were tested for their antitrypanosomal and anti-inflammatory activities against Trypanosome brucei gambiense and inhibition of carrageenan-induced rat paw edema. Compound 13f was the most potent antitrypanosomal agent with an IC50 value of 2 nM as against 5 nM for melarsoprol; whereas compound 13a was the most potent anti-inflammatory agent with percentage inhibition of carrageenan-induced rat paw edema of 58, 60, 67 and 84% after 0.5 h, 1 h, 2 h and 3 h administration respectively. The structure-activity relationship study revealed that substitution at the para position in the benzenesulfonamide ring increased both the antitrypanosomal and anti-inflammatory activities. The 4-hydroxyprolines (13a-d) showed higher anti-inflammatory activity than the prolines (13e-h). In contrast, the prolines (13e-h) had higher antitrypanosomal activities than the 4-hydroxyprolines. The link between excessive sleep and inflammation makes the report of this class of compounds possessing both antitrypanosomal and anti-inflammatory activity worthwhile. The pharmacokinetic studies showed that the compounds would not pose oral bioavailability, transport and permeability problems.