Antimalarial and antioxidant activities of novel artesunate-ellagic acid hybrid compound in vitro and in vivo.

Introduction: Emergence of drug resistant strains of Plasmodium species has necessitated the search for novel antimalarials with unique mechanisms of action. Synthesis of hybrid compounds has been one approach to tackling this challenge. In this study, the synthesis of artesunate-ellagic acid hybrid compound (EA31) from ellagic acid and artesunate and its evaluation for antimalarial and antioxidant activities using in vitro and in vivo models were carried out. Method: EA31 was synthesized from artesunate and ellagic acid. The activities of the hybrid compound against Plasmodium falciparum W2 and P. berghei NK65 were evaluated, and its antioxidant activities were also determined. Results: The results revealed that EA31 was more active against P. falciparum W2 (chloroquine resistant) clone and less cytotoxic to buffalo green monkey kidney cell line compared to artesunate. EA31 was also active against Plasmodium berghei NK65 in vivo. The results revealed inhibition of ß-hematin formation as one of the mechanisms of action of EA31. EA31 also exhibited antioxidant activities. Conclusion: The results revealed that EA31 may exert dual action of killing malaria parasite and mopping the reactive oxygen species that mediate the secondary complications of malaria.

Potentials of Terpenoids as Inhibitors of Multiple Plasmodium falciparum Protein Drug Targets.

PURPOSE: The resistance of parasite to readily affordable antimalarial drugs, the high cost of currently potent drugs, and the resistance of vector mosquitoes to insecticides threaten the possibility of malaria eradication in malaria endemic areas. Due to the fact that quinine and artemisinin were isolated from plants sources, researchers have been encouraged to search for new antimalarials from medicinal plants. This is especially the case in Africa where a large percentage of the population depends on medicinal plant to treat malaria and other ailments. METHOD: In this study, we evaluated previously characterized Plasmodium-cidal compounds obtained from the African flora to identify their likely biochemical targets, for an insight into their possible antimalarial chemotherapy. Molecular docking study was first conducted, after which remarkable compounds were submitted for molecular dynamic (MD) simulations studies. RESULTS: From a total of 38 Plasmodium-cidal compounds docked with confirmed Plasmodium falciparum protein drug targets [plasmepsin II (PMII), histo-aspartic protein (HAP) and falcipain-2 (FP)], two pentacyclic triterpene, cucurbitacin B and 3 beta-O-acetyl oleanolic acid showed high binding affinity relative to artesunate. This implies their capacity to inhibit the three selected P. falciparum target proteins, and consequently, antimalarial potential. From the MD simulations studies and binding free energy outcomes, results confirmed that the two compounds are stable in complex with the selected antimalarial targets; they also showed excellent binding affinities during the 100 ns simulation. CONCLUSION: These results showed that cucurbitacin B and 3 beta-O-acetyl oleanolic acid are potent antimalarials and should be considered for further studies.

Molecular basis for the repurposing of histamine H2-receptor antagonist to treat COVID-19.

With the world threatened by a second surge in the number of Coronavirus cases, there is an urgent need for the development of effective treatment for the novel coronavirus (COVID-19). Recently, global attention has turned to preliminary reports on the promising anti-COVID-19 effect of histamine H2-receptor antagonists (H2RAs), most especially Famotidine. Therefore, this study was designed to exploit a possible molecular basis for the efficacy of H2RAs against coronavirus. Molecular docking was performed between four H2RAs, Cimetidine, Famotidine, Nizatidine, Ranitidine, and three non-structural proteins viz. NSP3, NSP7/8 complex, and NSP9. Thereafter, a 100 ns molecular dynamics simulation was carried out with the most outstanding ligands to determine the stability. Thereafter, Famotidine and Cimetidine were subjected to gene target prediction analysis using HitPickV2 and eXpression2Kinases server to determine the possible network of genes associated with their anti-COVID activities. Results obtained from molecular docking showed the superiority of Famotidine and Cimetidine compared to other H2RAs with a higher binding affinity to all selected targets. Molecular dynamic simulation and MMPBSA results revealed that Famotidine as well as Cimetidine bind to non-structural proteins more efficiently with high stability over 100 ns. Results obtained suggest that Famotidine and Cimetidine could be a viable option to treat COVID-19 with a mechanism of action that involves the inhibition of viral replication through the inhibition of non-structural proteins. Therefore, Famotidineand Cimetidine qualify for further study as a potential treatment for COVID-19.

Phylogenic analysis of coronavirus genome and molecular studies on potential anti-COVID-19 agents from selected FDA-approved drugs.

The emergence of 2019 novel Coronavirus (COVID-19 or 2019-nCoV) has caused significant global morbidity and mortality with no consensus specific treatment. We tested the hypothesis that FDA-approved antiretrovirals, antibiotics, and antimalarials will effectively inhibit COVID-19 two major drug targets, coronavirus nucleocapsid protein (NP) and hemagglutinin-esterase (HE). To test this hypothesis, we carried out a phylogenic analysis of coronavirus genome to understand the origins of NP and HE, and also modeled the proteins before molecular docking, druglikeness, toxicity assessment, molecular dynamics simulation (MDS) and ligand-based pharmacophore modeling of the selected FDA-approved drugs. Our models for NP and HE had over 95% identity with templates 5EPW and 3CL5 respectively in the PDB database, with majority of the amino acids occupying acceptable regions. The active sites of the proteins contained conserved residues that were involved in ligand binding. Lopinavir and ritonavir possessed greater binding affinities for NP and HE relative to remdesivir, while levofloxacin and hydroxychloroquine were the most notable among the other classes of drugs. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of gyration (Rg), and binding energy values obtained after 100 ns of MDS revealed good stability of these compounds in the binding sites of the proteins while important pharmacophore features were also identified. The study showed that COVID-19 likely originated from bat, owing to the over 90% genomic similarity observed, and that lopinavir, levofloxacin, and hydroxychloroquine might serve as potential anti-COVID-19 lead molecules for additional optimization and drug development for the treatment of COVID-19.Communicated by Ramaswamy H. Sarma.

Evaluation of the gastrointestinal anti-motility effect of Anacardium occidentale stem bark extract: A mechanistic study of antidiarrheal activity.

Diarrhea is a prevalent gastrointestinal problem associated with fatal implications. It is a huge public health concern that requires better alternatives to current drugs. This study investigated the mechanisms involved in the antidiarrheal activity of Anacardium occidentale (Ao) stem bark extract, a plant commonly used in the management of diarrhea in Nigeria. Methanolic stem bark extract of the plant was partitioned into three fractions: hexane fraction, ethyl acetate fraction (AoEF) and methanol fraction. In vitro studies on the effect of these fractions on guinea pig ileum (GPI) strips, as well as the modulatory effect of AoEF on standard agonists- and antagonists-induced GPI contraction and relaxation, revealed AoEF as the most active fraction. In vivo studies to assess the effect of AoEF on the dopaminergic, muscarinic, and serotonergic pathways were carried out using gastric emptying (GE) and gastrointestinal transit (GT) as experimental end points. AoEF was subjected to GC-MS analysis, while the identified compounds were docked with the muscarinic acetylcholine receptor M3 (CHRM3) using AutodockVina. Results indicated that AoEF inhibited GE and GT via inhibition of CHRM3. In addition, GC-MS analysis revealed the presence of 24 compounds in AoEF, while docking indicated that octadecanoic acid 2-(2-hydroxylethoxy) ethyl ester exhibited the highest binding affinity to CHRM3. This study indicated that the antidiarrheal activity of Ao is through its antimotility effect via the inhibition of the muscarinic pathway. And since none of the identified compounds exhibited higher binding affinity to CHRM3 relative to loperamide, the antimotility activity of these phytoconstituents may be via synergism.

In Silico Screening Reveals Histone Deacetylase 7 and ERK1/2 as Potential Targets for Artemisinin Dimer and Artemisinin Dimer Hemisuccinate.

BACKGROUND: Recent studies have observed overexpression of histone deacetylase 7 (HDAC7) and overactivity of extracellular signal-regulated kinases 1/2 (ERK1/2) in many tumors; therefore, pharmacological interventions to inhibit overexpression of HDAC7 and overactivity of ERK1/2 in cancerous cells holds great promise in cancer treatment. The promising anticancer properties of artemisinin and artemisinin-derivatives (ARTs) have been validated by various experimental reports, including advanced pre-clinical trials. OBJECTIVE: Our aim in this in silico study is to identify additional inhibitors of HDAC7, ERK1 and ERK2 as potential anticancer drug agents and provide insight into the molecular level of interactions of such ligands relative to known standards. METHODS: To achieve this aim, the binding affinities of ulixertinib (the standard ERK inhibitor), apicidin (the standard HDAC7 inhibitor) as well as 49 ARTs for HDAC7, ERK1 and ERK2 were evaluated using AutodockVina. The molecular binding interactions of compounds with remarkable binding affinity for all the 3 target proteins, relative to their respective standards, were viewed with Discovery Studio Visualizer, BIOVIA, 2016. RESULTS: Out of the 49 ARTs, our study identified 2 compounds, artemisinin dimer and artemisinin dimer hemisuccinate, as having higher binding affinities for all the target proteins compared to their respective standard inhibitors. CONCLUSION: These findings suggest that artemisinin dimer and artemisinin dimer hemisuccinate could be promising anticancer drug agents, with better therapeutic efficacy than ulixertinib and apicidin for the treatment of cancer via inhibition of HDAC7, ERK1 and ERK2.