Structure-based virtual screening and molecular dynamics simulation studies to discover new SARS-CoV-2 main protease inhibitors.

Computational methods were used to filter two datasets (> 8,000 compounds) based on two criteria: higher binding affinity for MPRO than cocrystallized inhibitor and binding interactions with MPRO catalytic dyad (Cys145 and His41). After virtual screening involving ranking and reranking, eleven compounds were identified to satisfy these criteria and analysis of their structures revealed an unparallel common features among them which could be critical for their interactions with MPRO. However, only the topmost scoring compound (AV-203: K i = 0.31 µM) exhibited relatively stable binding interaction during the period of 50 ns MD simulation and thus is a suitable template for drug development.

Anti-Respiratory Syncytial Virus Compounds from Two Endophytic Fungi Isolated from Nigerian Medicinal Plants.

Background: Respiratory syncytial virus (RSV) is known to cause severe respiratory infections particularly in infants younger than 2 years of age. The only approved drug, ribavirin, is expensive and is not likely to improve therapeutic outcome, thereby necessitating the search for safer and more potent alternatives from natural sources such as endophytic fungi. The present study aimed to investigate the anti-RSV activity of compounds from endophytic fungi. Methods: Two endophytic fungi Colletotrichum gloeosporioides and Pestalotiopsis thea were isolated from the fresh leaves of the host Nigerian plants Anthocleista djalonensis and Fagara zanthoxyloides, respectively. After fermentation in solid rice media, C. gloeosporioides afforded 4 known compounds 4-hydroxybenzoic acid (1), vanillic acid (2), ferulic acid (3) and Nb-acetyltryptamine (4) while P. thea afforded 3 known compounds chloroisosulochrin (5), ficipyrone A (6) and pestheic acid (7). The compounds were investigated for their anti-RSV activity using the HEP-2 cell lines and ribavirin as the standard drug. Results: Compound 5 was found to show the strongest inhibition of the RSV with IC50 of 4.22±1.03 µM (ribavirin 4.91±1.85 µM). Other compounds showed moderate inhibition of the virus (IC50 ranging from 45.00±0.98 to 259.23±2.36 µM). Conclusion: The results of the present study have shown that chloroisosulochrin (5), isolated from an endophytic fungus P. thea, possesses strong activity against RSV.

Antitrypanosomal potentials of the extract and fractions of Abrus precatorius seeds.

OBJECTIVE: To evaluate the in vivo trypanocidal activity of the methanol extract and fractions of Abrus precatorius seeds in mice. METHODS: Parasiteamia was induced unto mice by intraperitoneal injection of 1.25×10(5)Trypanosoma in normal saline. Five days when a high level of parasiteamia was established treatment commenced until ten days. The mice were treated with 10, 20 and 40 mg/kg bt. of the extract and 5 and 10 mg/kg bt. of the fraction (F(2)), respectively for 5 days. Diminazene aceturate at the dose of 3.5 mg/kg bt. for two days was used as the reference drug. The level of parasitaemia and packed cell volume (PCV) of the animals estimated. RESULTS: At doses of 10, 20 and 40 mg/kg the crude extract showed a sharp reduction in the level of parasitaemia in mice compared with the untreated group. The mice treated with F(2) at doses of 5 and 10 mg/kg showed a sharp reduction in the level of parasitamia to zero in day 9, and a gradual recovery from the 12th day of treatment. This effect is comparable to that of the mice treated with 7 mg/kg of standard drug diminazene aceturate. The PCV of the treated showed a gradual decrease with time, but not as much as the untreated group. Phytochemical screening revealed the presence of glycosides, alkaloids, carbohydrates, tannins and proteins in the Abrus precatorius powder while F(2) was rich in alkaloids. CONCLUSIONS: This study shows that both the extract and the fractions of Abrus precatorius seeds exhibited a promising trypanocidal property. Alkaloids may be responsible for the observed activity.

In vitro and in vivo evaluation of the antitrypanosomal activity of fractions of Holarrhena africana.

The aqueous extract of young leaves of Holarrhena africana, a plant used in the Nigerian traditional medicine, exhibited good activity against Trypanosoma brucei spp. The extract was fractionated and eight fractions were obtained. One fraction designated as HaF(5) showed in vitro activity against Trypanosoma brucei rhodesiense with an IC(50) value of 0.785 microg/mg and no overt cytotoxicity against L-6 cells. Fraction HaF(5) was tested in vivo at two doses and found to exhibit in vivo efficacy in Trypanosoma brucei brucei infected mice leading to a complete disappearance of parasitaemia followed by a relapse.

Antimicrobial activities of some amino derivatives of 5, 7-dibromo-2-methyl-8-benzoyloxyquinoline.

In an attempt to design and synthesize more potent quinoline-based chemotherapeutic agents structural modifications of 5, 7-Dibromo-2-methyl-8-benzoyloxyqinoline was carried out. The replacement of the bromine atoms with the requisite alkylamino compound gave four amino-derivatives viz: bis(dipropylamino)-dipyrrolidino-, dipiperidino- and dipiperazino derivatives. The antimicrobial activities of these compounds were investigated against selected Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Escherichin coli, Pseudomonas aeruginosa and Klebsiella spp) and yeast (Candida albicans). All the compounds showed broad or significant antimicrobial activity, which varied from two to ninety times that of the parent compound. The dipyrrolidino derivative was the most effective against Gram-positive bacteria and yeast while the dipiperidino derivative was the most effective against Gram-negative bacteria. No correlation has been established between the minimum inhibitory, (MIC) concentrations of the derivatives and the structural modifications.