Evaluation of antiplasmodial activity of medicinal plants from North Indian Buchpora and South Indian Eastern Ghats.

BACKGROUND: Development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents. METHODS: Inspired by their ethnobotanical reputation for being effective against febrile diseases, antiplasmodial potential of ethyl acetate extracts (EAE) and methanol extracts (ME) of 17 medicinal plants collected from the Eastern Ghats of South India and Buchpora, North India were explored against Plasmodium falciparum in vitro using the SYBR Green assay. The results were validated both by confirmation that the fall in fluorescence signal was not due to quenching effects mediated by phytochemical extracts and by Giemsa-stained microscopy. RESULTS: Using EAE or ME, promising antiplasmodial activity (IC50 Pf3D7 ≤ 20 µg/ml), was seen in Aerva lanata (Whole aerial parts-EAE), Anisomeles malabarica (Leaf-EAE), Anogeissus latifolia (bark-EAE), Cassia alata (leaves-EAE), Glycyrrhiza glabra (root-EAE), Juglans regia (seed-ME), Psidium guajava (leaf-ME and EAE) and Solanum xanthocarpum (Whole aerial parts-EAE). EAEs from leaves of Couroupita guianensis, Euphorbia hirta, Pergularia daemia, Tinospora cordifolia and Tridax procumbens as also ME from Ricinus communis (leaf and seed) showed good antiplasmodial activity (Pf 3D7 IC50 21 - 40 µg/ml). Moderate activity (Pf 3D7 IC50: 40-60 µg/mL) was shown by the leaf EAEs of Cardiospermum halicacabum, Indigofera tinctoria and Ricinus communis while the remaining extracts showed marginal (Pf 3D7 IC50 60 to >100 µg/ml) activities. The promising extracts showed good resistance indices (0.41 - 1.4) against the chloroquine resistant INDO strain of P. falciparum and good selectivity indices (3 to > 22.2) when tested against the HeLa cell line. CONCLUSION: These results provide validity to the traditional medicinal usage of some of these plants and further make a case for activity-guided purification of new pharmacophores against malaria.

Anti-plasmodial action of de novo-designed, cationic, lysine-branched, amphipathic, helical peptides.

BACKGROUND: A lack of vaccine and rampant drug resistance demands new anti-malarials. METHODS: In vitro blood stage anti-plasmodial properties of several de novo-designed, chemically synthesized, cationic, amphipathic, helical, antibiotic peptides were examined against Plasmodium falciparum using SYBR Green assay. Mechanistic details of anti-plasmodial action were examined by optical/fluorescence microscopy and FACS analysis. RESULTS: Unlike the monomeric decapeptides {(Ac-GXRKXHKXWA-NH2) (X = F,ΔF) (Fm, ΔFm IC50 >100 µM)}, the lysine-branched,dimeric versions showed far greater potency {IC50 (µM) Fd 1.5 , ΔFd 1.39}. The more helical and proteolytically stable ΔFd was studied for mechanistic details. ΔFq, a K-K2 dendrimer of ΔFm and (ΔFm)2 a linear dimer of ΔFm showed IC50 (µM) of 0.25 and 2.4 respectively. The healthy/infected red cell selectivity indices were >35 (ΔFd), >20 (ΔFm)2 and 10 (ΔFq). FITC-ΔFd showed rapid and selective accumulation in parasitized red cells. Overlaying DAPI and FITC florescence suggested that ΔFd binds DNA. Trophozoites and schizonts incubated with ΔFd (2.5 µM) egressed anomalously and Band-3 immunostaining revealed them not to be associated with RBC membrane. Prematurely egressed merozoites from peptide-treated cultures were found to be invasion incompetent. CONCLUSION: Good selectivity (>35), good resistance index (1.1) and low cytotoxicity indicate the promise of ΔFd against malaria.

Exploration of Anti-plasmodial Activity of Prunus cerasoides Buch.-Ham. ex D. Don (family: Rosaceae) and Its Wood Chromatographic Fractions.

PURPOSE: Increasing resistance to the currently available antimalarial drugs is a leading cause of failure to control malaria. Plant-based medicines are commonly used to manage numerous infections, making medicinal plants the best possible source of alternative antimalarial drugs. The objective of this study is therefore to identify antimalarial potential of Prunus cerasoides. METHODS: Here, anti-plasmodial activity of crude methanolic and aqueous extracts of Prunus cerasoides and fractions obtained by reverse-phase high performance liquid chromatography (RPHPLC) were tested for in vitro activity against chloroquine sensitive Plasmodium falciparum 3D7 and chloroquine resistant INDO & Dd2 strains using SYBR Green I assay. The cytotoxic activity of active extracts/fractions was evaluated against mammalian cell lines-HeLa using MTT assay. RESULTS: Aqueous extracts of leaves, wood, bark and fruit of P. cerasoides showed poor to no activity up to 100 µg/ml, however methanolic extract showed moderate (IC50: 21-60 µg/ml) to poor (IC50: 61-100 µg/ml) anti-plasmodial activity. Fractionation of wood methanolic extract led to enrichment in antimalarial activity in some of its fractions as out of 17 fractions collected, good anti-plasmodial activity (IC50: 1-20 µg/ml) was shown by three fractions and nine fractions showed moderate anti-plasmodial activity. However, five fractions showed poor to no activity against Plasmodium falciparum (IC50:61-100 and >100 µg/ml respectively). Furthermore, these active fractions showed no cytotoxic effects on mammalian cell lines. CONCLUSION: Findings of this study elucidate the anti-plasmodial potential of P. cerasoides and validate its traditional usage suggesting that it could be a possible source of a drug candidate in combating this disease.

In silico Potential of Approved Antimalarial Drugs for Repurposing Against COVID-19.

Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (MPro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.

Pyrano[4,3-b]quinolines library generation via iodocyclization and palladium-catalyzed coupling reactions.

Synthesis of a 80-member library of novel pyrano[4,3-b]quinolines in solution-phase is reported. The key intermediate, 4-iodopyrano[4,3-b]quinolines were synthesized by the electrophilic iodocyclization of corresponding ortho-alkynyl aldehydes in good to excellent yields under mild reaction conditions. Subsequently a diverse set of libraries was generated by employing palladium-catalyzed Suzuki-Miyaura, Heck, and Sonogashira coupling reactions on 4-iodopyrano[4,3-b]quinolines. In this way, a series of structurally different and biologically interesting molecules were obtained. Some of the selected compounds were screened against 3D7 strains of Plasmodium falciparum for antimalarial activity. Suzuki coupling products 6{3} and 6{21} and Heck coupling product 8{12} exhibit promising antimalarial activity.