High Antimalarial Activity Research Articles

Novel ether derivatives of 11-azaartemisinins with high order antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice

This study investigates cutting-edge synthetic chemistry approaches for designing and producing innovative antimalarial drugs with improved efficacy and fewer adverse effects. Novel amino (–NH2) and hydroxy (–OH) functionalized 11-azaartemisinins 9, 12, and 14 were synthesized along with their derivatives 11a, 13a-e, and 15a-b through ART and were tested for their AMA (antimalarial activity) against Plasmodium yoelii via intramuscular (i.m.) and oral routes in Swiss mice. Ether derivative 13c was the most active compound by i.m. route, it has shown 100 % protection at the dose of 12 mg/kg × 4 days and showed 100 % clearance of parasitaemia on day 4 at dose of 6 mg/kg. Amine 11a, ether derivatives 13d, 13e and ether 15a also showed promising antimalarial activity. β-Arteether gave 100 % protection at the dose of 48 mg/kg × 4 days and 20 % protection at 24 mg/kg × 4 days dose by oral route, while it showed 100 % protection at 6 mg/kg × 4 days and no protection at 3 mg/kg × 4 days by i.m. route.

Assessment of antimalarial activity of crude extract of Chan-Ta-Lee-La and Pra-Sa-Chan-Dang formulations and their plant ingredients for new drug candidates of malaria treatment: In vitro and in vivo experiments.

The emergence and spread of antimalarial drug resistance have become a significant problem worldwide. The search for natural products to develop novel antimalarial drugs is challenging. Therefore, this study aimed to assess the antimalarial and toxicological effects of Chan-Ta-Lee-La (CTLL) and Pra-Sa-Chan-Dang (PSCD) formulations and their plant ingredients. The crude extracts of CTLL and PSCD formulations and their plant ingredients were evaluated for in vitro antimalarial activity using Plasmodium lactate dehydrogenase enzyme and toxicity to Vero and HepG2 cells using the tetrazolium salt method. An extract from the CTLL and PSCD formulations exhibiting the highest selectivity index value was selected for further investigation using Peter's 4-day suppressive test, curative test, prophylactic test, and acute oral toxicity in mice. The phytochemical constituents were characterized using gas chromatography-mass spectrometry (GC-MS). Results showed that ethanolic extracts of CTLL and PSCD formulations possessed high antimalarial activity (half maximal inhibitory concentration = 4.88, and 4.19 g/mL, respectively) with low cytotoxicity. Ethanolic extracts of the CTLL and PSCD formulations demonstrated a significant dose-dependent decrease in parasitemia in mice. The ethanolic CTLL extract showed the greatest suppressive effect after 4 days of suppressive (89.80%) and curative (35.94%) testing at a dose of 600 mg/kg. Moreover, ethanolic PSCD extract showed the highest suppressive effect in the prophylactic test (65.82%) at a dose of 600 mg/kg. There was no acute toxicity in mice treated with ethanolic CTLL and PSCD extracts at 2,000 mg/kg bodyweight. GC-MS analysis revealed that the most abundant compounds in the ethanolic CTLL extract were linderol, isoborneol, eudesmol, linoleic acid, and oleic acid, whereas ethyl 4-methoxycinnamate was the most commonly found compound in the ethanolic PSCD extract, followed by 3-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-4H-chromen-4-one, flamenol, oleic acid amide, linoleic acid, and oleic acid. In conclusions, ethanolic CTLL and PSCD extracts exhibited high antimalarial efficacy in vitro. The ethanolic CTLL extract at a dose of 600 mg/kg exhibited the highest antimalarial activity in the 4-day suppressive and curative tests, whereas the ethanolic PSCD extract at a dose of 600 mg/kg showed the highest antimalarial activity in the prophylactic test.

Solubility enhancing lipid-based vehicles for artemether and lumefantrine destined for the possible treatment of induced malaria and inflammation: in vitro and in vivo evaluations

BackgroundThe lipid self-emulsifying system has been advanced as a promising delivery vehicle for improving the solubility and bioavailability of artemether and lumefantrine. However, the observed kinetic instability (propensity of lumefantrine to rapid crystallisation from nano-scale droplets) in aqueous acid has impelled some researchers to incorporate surfactants/solubilizers in the dissolution medium prior to dissolution studies. Thus, in our present work, we sought to prepare micro/large nano-scale (> 100 nm) and yet kinetically stable lumefantrine lipid self-emulsifying system (that would not require an external drug dissolution enhancing agent in the dissolution medium) and palm kernel oil-based 100 nm kinetically stable artemether lipid self-emulsifying system with rapid emulsification time. COVID-19 and Plasmodium falciparum-infected Africans with previous long exposure to malaria have manifested attenuated inflammatory cytokines more than malaria-naive patients. Therefore, the ingestion of artemether-lumefantrine with enhanced solubility may further promote blunting of cytokines. Therefore, this work was aimed at preparing (< 100 nm) stable artemether and aqueous acid-stable micro/large nano-scale (> 100 nm) lumefantrine lipid self-emulsifying system destined for improved antimalarial and anti-inflammatory activities.ResultsThe droplet sizes of all the liquid artemether and lumefantrine formulations were between 8.95–39.88 and 1018–4195 nm, respectively. The loading efficiency for all the formulations was, between 72.91 ± 2.89 and 100.00 ± 0.29%. All the artemether and lumefantrine batches emulsified within the range of 3.90 ± 0.69 to 12.26 ± 0.69 s. Stable and transparent emulsions were formed on aqueous dilution to 1000 ml. The percentage drug released for artemether and lumefantrine ranged from 76.25 ± 2.98 to 99.22 ± 1.61%. The solid lipid self-emulsifying systems produced, had fair and passable flow properties. Differential scanning calorimetry revealed that the solid artemether and lumefantrine lipid self-emulsifying system were amorphous. Solidification with Neusilin FH2 or surfactant replacement with Kolliphor EL and Kollidon VA 64 fine prevented micro-or large nano-scale lumefantrine lipid self-emulsifying system from crystallisation in aqueous acid (pH 1.2). Higher antimalarial activity and remarkable anti-inflammatory effects (P < 0.05) favoured the lipid self-emulsifying formulations.ConclusionOptimal in vitro and in vivo results (enhanced antimalarial and anti-inflammatory activities) were obtained with kinetically stable lumefantrine micro/large nano-scale droplets and kinetically stable palm kernel oil-based (< 50 nm) artemether lipid self-emulsifying system droplets.

Discovery of Potential Prolyl-tRNA Synthetase Allosteric Inhibitor Through Virtual Screening and In Vitro Assay against Plasmodium falciparum

Objectives: This study aimed to identify novel antimalarial compounds based on allosteric inhibitor of prolyl-tRNA synthetase using hierarchical virtual screening. Materials and Methods: Pharmacophore model was designed initially, based on the structure-activity relationships data between several pyrazole-urea analogues and their IC50 enzymatic value. The model obtained was applied to screen ZINC15 database, after which followed by drug-likeness, toxicophore, and PAINS filter. The hit compounds were docked against P. falciparum prolyl-tRNA synthetase enzyme, using validated docking method. The resulting docking poses were ranked based on the docking score and re-evaluated based on the pharmacophore criteria. Top five compounds were obtained from this step and then evaluated using molecular dynamics simulation to verify its stability and hydrogen bond dynamics over 50 nanoseconds. MM-PBSA analysis was also performed to estimate their binding free energy. Ultimately, their potential bioactivity as antimalarial candidates have been verified against 3D7 strain. Results: The results showed that all five compounds obtained from virtual screening possess micromolar potency in vitro. Two compounds (ZINC 1029449 and ZINC1029453), yield high antimalarial activity (0.44 and 0.72 μM, respectively) Conclusions: Overall, the virtual screening approach has successfully produced lead compounds which can be further optimized to be antimalarial agents.

Targeting antimalarial metabolites from the actinomycetes associated with the Red Sea sponge Callyspongia siphonella using a metabolomic method

Malaria is a persistent illness that is still a public health issue. On the other hand, marine organisms are considered a rich source of anti‑infective drugs and other medically significant compounds. Herein, we reported the isolation of the actinomycete associated with the Red Sea sponge Callyspongia siphonella. Using "one strain many compounds" (OSMAC) approach, a suitable strain was identified and then sub-cultured in three different media (M1, ISP2 and OLIGO). The extracts were evaluated for their in-vitro antimalarial activity against Plasmodium falciparum strain and subsequently analyzed by Liquid chromatography coupled with high-resolution mass spectrometry (LC-HR-MS). In addition, MetaboAnalyst 5.0 was used to statistically analyze the LC-MS data. Finally, Molecular docking was carried out for the dereplicated metabolites against lysyl-tRNA synthetase (PfKRS1). The phylogenetic study of the 16S rRNA sequence of the actinomycete isolate revealed its affiliation to Streptomyces genus. Antimalarial screening revealed that ISP2 media is the most active against Plasmodium falciparum strain. Based on LC-HR-MS based metabolomics and multivariate analyses, the static cultures of the media, ISP2 (ISP2-S) and M1 (M1-S), are the optimal media for metabolites production. OPLS-DA suggested that quinone derivatives are abundant in the extracts with the highest antimalarial activity. Fifteen compounds were identified where eight of these metabolites were correlated to the observed antimalarial activity of the active extracts. According to molecular docking experiments, saframycin Y3 and juglomycin E showed the greatest binding energy scores (-6.2 and -5.13) to lysyl-tRNA synthetase (PfKRS1), respectively. Using metabolomics and molecular docking investigation, the quinones, saframycin Y3 (5) and juglomycin E (1) were identified as promising antimalarial therapeutic candidates. Our approach can be used as a first evaluation stage in natural product drug development, facilitating the separation of chosen metabolites, particularly biologically active ones.

Anti-malarial and haematological evaluation of the ethanolic, ethyl acetate and aqueous fractions of Chromolaena odorata

Malaria is a global health challenge with endemicity in sub-Saharan Africa, where there are multiple drug-resistant strains and limited access to modern health care facilities, especially in rural areas. Studies indicate that African traditional medicine could make a substantial contribution to the reduction of malaria-related deaths and achievement of universal health coverage (UHC), particularly in these regions. Thus, this study evaluated the curative antimalarial effects of Chromolaena odorata leaf extract using mouse model. Forty-five (45) albino mice weighing between 18 and 22 g were grouped into nine groups of 5 animals each. Animals in groups 2–9 were infected with the chloroquine-resistant strain of Plasmodium berghei, while animals in groups 3–9 were subsequently treated with 10 mg/kg chloroquine, a combination of 1.4 mg/kg artemether and 8.75 mg/kg lumefantrine (Coartem), and varying concentrations of the fraction from the aqueous leaf extract of C. odorata at day 3 post-infection. The findings from this study indicate that treatment with 400 mg/kg of the ethanolic fraction of the crude extract resulted in a significant decrease in parasite load (97.6%), which was comparable to the activities of the conventional drugs chloroquine (98.6%) and Coartem (98.8%). The ethyl acetate and ethanolic fractions at 400 mg/kg also ameliorated the significant alterations in the red blood cells, white blood cells, and platelets of the infected animals. The high antimalarial activity displayed by the ethanolic fraction could be due to the presence of quercetin and kaempferol, as detected by high performance liquid chromatography (HPLC) analysis. The findings suggest that the fractions from C. odorata could serve as an alternative source of malaria therapy, particularly in sub-Saharan Africa.

Terpenoids from Euphorbiaceae as a source of antimalarial medicines: A literature review

Background: Malaria is an infectious disease caused by the Plasmodium parasite and transmitted by the Anopheles mosquito. Plasmodium falciparum is a parasite that causes the most deaths. Currently, there is resistance to various antimalarial drugs. For this reason, it is necessary to search for new antimalarial agents. Medicinal plants have been shown to play an important role in treating malaria for thousands of years. Some of Euphorbiaceae family plants contains terpenoid compounds, which are compounds with antimalarial activity. Objective: The present review aims to provide an overview of the terpenoid compounds from Euphorbiaceae family as an antimalarial. Method: Comprehensive information on Euphorbiaceae family from 2002-2022 was searched for literature relevant to major science-based data, including Scopus, Science, ScienceDirect, Pubmed, and SciFinder, using appropriate keyword combinations. Result: A total of 15 papers were included in this review. The terpenoids isolated from 14 species of Euphorbiaceae family and reported to possess antimalarial activity are presented. Conclusion: Terpenoids are found in almost all parts of Euphorbiaceae family plants and are reported to have moderate to high antimalarial activity. Screening of antimalarial terpenoid activity in Ephorbiaceae family plants can be a key step in the source and development of new antimalarial drugs.

SYNTHESIS OF TERMINAL 2-ALKENYL(ALKYNYL)THIO-5-CYANO-6-(p-DIMETHYLAMINOPHENYL)PYRIMIDIN-4-ONES

Functionalized pyrimidines possess a wide spectrum of biological activity. In particular, they have antitumor, antiviral, and anticonvulsant activities, exhibit anti-inflammatory and analgesic effects, and they are inhibitors of aldose reductase, SecA ATPase, azide, and plant growth. The search for methods of synthesis of new functionalized and condensed pyrimidine derivatives is an urgent problem.&#x0D; Alkenyl-functionalized mono- and polycyclic pyrimidines are promise substrates for studying the regioselectivity of electroph ilic heterocyclization reactions under the influence of halogen-containing electrophilic agents, and halogen- and chalcogen-functionalized cyclization products showed high antibacterial, antifungal, and antimalarial activity. The introduction of new functional groups capable to modification into such alkenylpyrimidines can significantly affect their reactivity and change/enhance the biological activity of the halocyclization products. We proposed the synthesis of 2-alkenyl(alkynyl)thio derivatives of 5-cyano-6-(p-dimethylaminophenyl)-pyrimidin-4-one containing a cyano group labile to functionalization. As a result of alkylation of 2-thioxo-5-cyano-6-(p-dimethylaminophenyl)pyrimidin-4-one with unsaturated alkyl halides in an alkaline medium, the terminal alkenyl (allyl, methallyl) and alkynyl (propargyl) thioethers of cyanopyrimidine were obtained, promising for heterocyclization with halogen-containing electrophilic reagents .&#x0D; Keywords: 2-thioxo-5-cyano-pyrimidin-4-one; alkylation; alkenylthiopyrimidinone; alkynylthiopyrimidinone.

Bioactivity assays and phytochemical analysis upon Achillea filipendulina, focusing on xanthine oxidase inhibitory and antimalarial properties

BackgroundAchillea filipendulina (L.) is an important medicinal plant and an Asian species of the Asteraceae family. A. filipendulina that grows in Central and Southwest Asia. It was chosen for study with the aim of screening biologically active compounds in the essential oil of the aerial parts and the antioxidant, antimalarial and xanthine oxidase inhibitory activities of its extract. Essential oil was extracted by using Clevenger apparatus. Extraction was done by Soxhlet apparatus with solvents of n-hexane, DCM (dichloromethane) and MeOH (methanol), and then, fractionation of extracts was accomplished through various chromatographic techniques including VLC (vacuum liquid chromatography) approach and SPE (solid phase extraction) technique.ResultsApproximately 79% of A. filipendulina essential oil components were recognized by the gas chromatography mass spectrometry (GC–MS), of which monoterpenes were 63.2% the most abundant components, except for terpenes, other compounds such as fatty acids, phenols, aromatic compounds and ketones were identified, as well antimalarial activity test was done by β-hematin formation assay and xanthine oxidase inhibitory activity was accomplished by Ransod kit, then antioxidant activity was performed by DPPH (2,2-diphenyl 1-picrylhydrzyl) free radical scavenging technique. Preliminary phytochemical screening of MeOH and DCM extracts was done by TLC (thin layer chromatography) and total phenol assay. Monoterpenoids were the main component of the aerial part’s essential oil. Among different extracts, MeOH extract had significant antioxidant and xanthine oxidase inhibitory activities with RC50 (mg/mL) = 0.0707 and IC50 = 12.8741 µg/mL, respectively. Moreover DCM extract had significant antimalarial activities with IC50 (mg/mL) = 0.2511. Among the fractions, 40% and 60% Sep-Pak fraction of MeOH extract had stronger xanthine oxidase inhibitory and antioxidant activities. The 40% fraction of MeOH extract showed the strongest antioxidant and xanthine oxidase inhibitory activities, which might be related to the presence of phenolic compounds. The 80% VLC fraction of DCM extract also indicated the strong antimalarial activities.ConclusionAs this plant revealed a high content of phenols along with high antioxidant, antimalarial and xanthine oxidase inhibitory activities, it could have great medicinal value. Our results suggested the possible use of A. filipendulina in development of highly potent new pure medicinal compounds.

Curry Fish Extract's Antimalarial Potency in N-hexane and Ethyl Acetate Solvents using In vitro approach

The increase in malaria morbidity and mortality due to artemisinin derivative resistance was a global problem. Marine biota, curry fish or Sticophus hermanni was known to have bioactive components that are antibacterial and antifungal. The purpose of the study was to observe phytochemical tests and antimalarial activity of golden sea cucumber, curry fish using two types of solvents with different polarities using In vtro studies. The study was a true experimental study withIn vtro protocols, which included: (P1), control negative; (P2) P. falciparum medium with n-hexane extract of curry fish; (P3) P.falciparum medium with ethyl acetate extract of curry fish. The parameters were as follows: phytochemical assay, growth %, inhibitory rate, and IC50. The phytochemical analysis found various bioactive components in the ethyl acetate extract, including flavonoids, alkaloids, steroids, and tannins, whereas the n-hexane extract includes fewer active components, including flavonoids, alkaloids, steroids, and tannins. The extract's antimalarial action is demonstrated by a decrease in parasite growth, a rise in the inhibitory rate with increasing extract dose, and IC50 less than 5 µg/ml when administered with ethyl acetate and n-hexane. Both solvents in curry fish extract displayed high antimalarial activity; however, n-hexane had a lower IC50 than ethyl acetate.

Antimalarial efficacy and toxicological assessment of medicinal plant ingredients of Prabchompoothaweep remedy as a candidate for antimalarial drug development

BackgroundDrug resistance exists in almost all antimalarial drugs currently in use, leading to an urgent need to identify new antimalarial drugs. Medicinal plant use is an alternative approach to antimalarial chemotherapy. This study aimed to explore potent medicinal plants from Prabchompoothaweep remedy for antimalarial drug development.MethodsForty-eight crude extracts from Prabchompoothaweep remedy and its 23 plants ingredients were investigated in vitro for antimalarial properties using Plasmodium lactate dehydrogenase (pLDH) enzyme against Plasmodium falciparum K1 strain and toxicity effects were evaluated in Vero cells. The plant with promising antimalarial activity was further investigated using gas chromatography-mass spectrometry (GC-MS) to identify phytochemicals. Antimalarial activity in mice was evaluated using a four-day suppressive test against Plasmodium berghei ANKA at dose of 200, 400, and 600 mg/kg body weight, and acute toxicity was analyzed.ResultsOf the 48 crude extracts, 13 (27.08%) showed high antimalarial activity against the K1 strain of P. falciparum (IC50 < 10 μg/ml) and 9 extracts (18.75%) were moderately active (IC50 = 11–50 μg/ml). Additionally, the ethanolic extract of Prabchompoothaweep remedy showed moderate antimalarial activity against the K1 strain of P. falciparum (IC50 = 14.13 μg/ml). Based on in vitro antimalarial and toxicity results, antimalarial activity of the aqueous fruit extract of Terminalia arjuna (IC50 = 4.05 μg/ml and CC50 = 219.6 μg/ml) was further studied in mice. GC-MS analysis of T. arjuna extract identified 22 compounds. The most abundant compounds were pyrogallol, gallic acid, shikimic acid, oleamide, 5-hydroxymethylfurfural, 1,1-diethoxy-ethane, quinic acid, and furfural. Analysis of the four-day suppressive test indicated that T. arjuna extract at dose of 200, 400, and 600 mg/kg body weight significantly suppressed the Plasmodium parasites by 28.33, 45.77, and 67.95%, respectively. In the acute toxicity study, T. arjuna extract was non-toxic at 2000 mg/kg body weight.ConclusionsThe aqueous fruit extract of T. arjuna exerts antimalarial activity against Plasmodium parasites found in humans (P. falciparum K1) and mice (P. berghei ANKA). Acute toxicity studies showed that T. arjuna extract did not show any lethality or adverse effects up to a dose of 2000 mg/kg.

Naturally occurring phenylethanoids and phenylpropanoids: antimalarial potential.

Malaria as an infectious disease is one of the world's most dangerous parasitic diseases. There is an urgent need for the development of new antimalarial drugs. Natural products are a very rich source of new bioactive compounds. Our research aims to shed light on the recent studies which demonstrated the antimalarial potential of phenylpropanoids as a major natural-products class. This study involves an in silico analysis of naturally-occurring phenylpropanoids and phenylethanoids which showed 25 compounds with moderate to strong binding affinity to various amino acid residues lining the active site; P. falciparum kinase (PfPK5), P. falciparum cytochrome bc1 complex (cyt bc1), and P. falciparum lysyl-tRNA synthetase (PfKRS1); of Plasmodium falciparum parasite, a unicellular protozoan which causes the most severe and life-threatening malaria. Furthermore, the study was augmented by the assessment of antiplasmodial activity of glandularin, a naturally occurring dibenzylbutyrolactolic lignan, against chloroquine-sensitive 3D7 strain of P. falciparum using SYBR green I-based fluorescence assay, which showed high antimalarial activity with IC50 value of 11.2 μM after 24 hours of incubation. Our results highlight phenylpropanoids and glandularin in particular as a promising chemical lead for development of antimalarial drugs.

Design and development of novel N-(4-aminobenzoyl)- l-glutamic acid conjugated 1,3,5-triazine derivatives as Pf-DHFR inhibitor: An in-silico and in-vitro study.

In the present work, a library of 120 compounds was prepared using various aliphatic and aromatic amines. Finally, 10 compounds were selected through in silico screening carrying 4-aminobenzoyl-l-glutamic acid and 1,3,5-triazine moiety. The docking results of compounds 4d16 and 4d38 revealed higher binding interaction with amino acids Asp54 (-537.96 kcal/mol) and Asp54, Phe116 (-618.22 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR inhibitors and were comparable to standard WR99210. These compounds were developed by facile and microwave-assisted synthesis via nucleophilic substitution reaction and characterized by different spectroscopic methods. In vitro antimalarial assay results also suggested that these two compounds were having higher antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain out of the ten synthesized compounds with IC50 13.25 μM and 14.72 μM, respectively. These hybrid scaffolds might be useful in the lead discovery of a new class of Pf-DHFR inhibitors.

Evaluation of Chiral Organosulfur Compounds on Their Activity against the Malaria Parasite Plasmodium falciparum.

Malaria is one of the deadliest tropical diseases, especially causing havoc in children under the age of five in Africa. Although the disease is treatable, the rapid development of drug resistant parasites against frontline drugs requires the search for novel antimalarials. In this study, we tested a series of organosulfur compounds from our internal library for their antiplasmodial effect against Plasmodium falciparum asexual and sexual blood stages. Some active compounds were also obtained in enantiomerically pure form and tested individually against asexual blood stages of the parasite to compare their activity. Out of the 23 tested compounds, 7 compounds (1, 2, 5, 9, 15, 16, and 17) exhibited high antimalarial activity, with IC50 values in the range from 2.2 ± 0.64 to 5.2 ± 1.95 µM, while the other compounds showed moderate to very low activity. The most active compounds also exhibited high activity against the chloroquine-resistant strain, reduced gametocyte development and were not toxic to non-infected red blood cells and Hela cells, as well as the hematopoietic HEL cell line at concentrations below 50 µM. To determine if the enantiomers of the active compounds display different antimalarial activity, enantiomers of two of the active compounds were separated and their antimalarial activity compared. The results show a higher activity of the (-) enantiomers as compared to their (+) counterparts. Our combined data indicate that organosulfur compounds could be exploited as antimalarial drugs and enantiomers of the active compounds may represent a good starting point for the design of novel drugs to target malaria.

Quantitative Structure Activity Relationship (QSAR) Investigations and Molecular Docking Analysis of Plasmodium Protein Farnesyltransferase Inhibitors as Potent Antimalarial Agents

The development of farnesyltransferase inhibitors based on the benzophenone scaffold directed against Plasmodium falciparum is considered a strategy in malaria treatment. In this work, quantitative structure–activity relationship (QSAR) was performed to predict the protein farnesyltransferase (PFT) inhibitory activities for a series of 36 benzophenone derivatives. The data set was divided into two subsets of training and test sets, and the best model using multiple linear regression (MLR), with the values of internal and external validity (R2 = 0.884, R2adj = 0.865, R2pred = 0.821, Q2cv =0.822 and R2p=0.811) was found in agreement with the Tropsha and Golbraikh criteria. The applicability domain (AD) was determined using the Williams plot to describe the chemical space for the model used in this study. The model shows that antimalarial activities of benzophenone depend on logP, bpol, MAXDn, and FMF descriptors. These indications prompted us to design new benzophenones PFT inhibitors and predict the value of their anti-malarial activities based on the MLR equation. Docking results reveal that the newly designed benzophenones bind to the hydrophobic pocket and polar contact with high affinity. The predicted results from this study can help to design novel benzophenone as inhibitors of human PFT with high antimalarial activities.

Synthesis, antimalarial activity assay and molecular docking study of N-substituted chloro-pyrazolines

Purpose: To synthesize chloro-pyrazolines (A–D), determine their antimalarial activity against Plasmodium falciparum strain 3D7 in vitro, and understand the interaction between falcipain-2 active sites and synthesized compounds by molecular docking simulation.Methods: Chloro-pyrazolines (A–D) were synthesized via cyclo-condensation of 4-chloro chalcone derivatives using several types of hydrazines, i.e., formylhydrazine, benzoylhydrazine, phenylhydrazine and chlorophenylhydrazine. The compounds were analyzed and subjected to antimalarial assay against P. falciparum 3D7. Molecular docking was performed using AutoDock Tools and AutoDock Vina, while each docked compound was visualized using Discovery Studio Visualizer.Results: Pyrazolines A–D yield was 87.09, 61.71, 50.24 and 57.64 %, respectively. Antimalarial assay showed half-maximal inhibitory concentration (IC50) values of 16.46 and 5.55 μM for pyrazoline A and B, respectively, and ≥ 100 μM for pyrazoline C and D. Molecular docking study revealed that pyrazolines A–D had good interaction with the active site of falcipain-2 receptor.Conclusion: A series of N-substituted chloro-pyrazolines has successfully been synthesized with moderate yield. Pyrazoline B has the highest antimalarial activity against P. falciparum 3D7 with IC50 of 5.55 μM. This finding is supported by molecular docking and indicates that the benzoyl substituent increases the antimalarial activity of pyrazoline B. Pyrazoline B has potentials for clinical application as an antimalaria agent.

Synthesis of 1,5-diaryl-2-fluoro-6,7-dioxabicyclo[3.2.2]nonanes with high antimalarial activity utilizing photoinduced electron-transfer oxygenation reactions

1,5-Diaryl-2-fluoro-6,7-dioxabicyclo[3.2.2]nonanes were synthesized from corresponding 3-fluoro-2,6-diarylhepta-1,6-dienes utilizing 2,4,6-triphenylpyrylium salt (TPPX: X = BF4, ClO4)-sensitized photoinduced electron-transfer (PET) oxygenation reactions, and their in-vitro antimalarial activity was evaluated. Results showed that these fluorinated bicyclic peroxides had higher antimalarial activity than their nonfluorinated parent bicyclic peroxides. In addition, it was shown that PET oxygenation reactions, particularly TPPX-biphenyl-cosensitized PET oxygenation reactions, are an efficient method for the construction of a COOC structure during the synthesis of fluorinated antimalarial bicyclic peroxides.

ANTIMALARIAL, ANTI-TERMITE, AND ANTIFUNGAL ACTIVITIES FROM EXTRACT OF THE ROOT OF Lansium domesticum CORR.

Phytochemical screening of the crude extract and their fractions from the root of L. domesticum exhibited various groups of secondary metabolites. The root powder was macerated by methanol, then the crude extract was stepwise partitioned with n-hexane and chloroform. The crude extract and all fractions were phytochemically tested for alkaloids, terpenoids, flavonoids, and phenolics, and it was evaluated for antimalarial, anti-termite, and antifungal activities. The results revealed that at 5% (w/v) chloroform fraction which contained flavonoids and triterpenoids showed high antimalarial activity against Plasmodium falciparum with IC50 value 1.4 g/mL and methanol fraction at a concentration of 5% (w/v) which contained phenolics showed anti-termite and antifungal activities by 100% mortality against Coptotermes curvignathus and 100% inhibition to fungal mycelia growth of Tyromyces palustris (TYP), respectively.

Anti-Malarial Activity and Toxicological Effect of Combined Corymbia Citriodora, Maytenus Senegalensis and Warbugia Ugandensis as Used in Traditional Medicine in Kenya

Malaria is majorly caused by Plasmodium falciparum resulting in thousands of deaths every year. In Africa, it is a key contributor to the disease burden notable in the disability adjusted life years (DALYs). About 243 million individuals are at a risk of contracting the disease and a higher rate of deaths are observed in children under the age of five. Conventional drugs are available at a subsidized rate but the rising problem is the resistance of the plasmodium parasite to these drugs. Hence, there is an urgent need for the development of new and alternative therapeutics for treatment of malaria. In some regions in Kenya, parts of locally available plants are harvested and used for treating malaria. It is estimated that locally, 30% of the population relies on traditional medicine for treating various ailments due to the lack of infrastructure and accessible medical facilities especially in the rural areas. Warbugia ugandensis , Maytenus senegalensis and Corymbia citriodora are amongst the plants used in herbal medicine for the treatment of malaria. However, their combinatorial antimalarial efficacy and safety is yet to be determined hence the aim of this study. The plants were harvested from their natural habitats and transported to the Centre of Traditional Medicine and Drug Research (CTMDR) at the Kenya Medical Research Institute (KEMRI), Nairobi. Antimalarial properties of single and combined extracts were analyzed against Plasmodium berghei in vivo . Cytotoxic properties of the plants were carried out against the vero cell-lines in vitro by the MTT assay. Acute oral toxicity was conducted according to the OECD protocol. Effective concentration (ED 50 ), cytotoxicity concentration (CC 50 ) and median lethal dose (LD50) were derived. The result indicated that the combination of M. senegalensis : W. ugandensis (1:1) had the most antimalarial activity at ED 50 of 1.05mg/kg whereas among the single plants W. ugandensis had the highest antimalarial activity (ED 50 of 3.3mg/kg). The combinations of C. citriodora : M. senegalensis : W. ugandensis (1:1:1), C. citriodora : M. senegalensis : W. ugandensis (1:0.5:1) and C. citriodora : M. senegalensis : W. ugandensis (0.5:1:0.5) showed cytotoxicity concentration (CC 50 ) of 101.47±3.17 µg/ml, 213.55±3.47 µg/ml and 575.80±31.40 µg/ml respectively. A ll the plants combinations showed no cytotoxic effects. The synergistic antimalarial properties of combined C. citriodora : M. senegalensis , C. citriodora : W. ugandensis and M. senegalensis : W. ugandensis were confirmed as the extracts showed SFIC indexes of 0.67, 0.83 and 0.28 respectively. All the plant extracts demonstrated LD 50 above 2000 mg/kg with no adverse effects hence recognized as safe. This study confirms the safety and antimalarial activities of these plants and justify their use in herbal medicine practices. The results of this study sets the precedence for the development of an antimalarial herbal formulation that is less toxic and more affordable. Keywords : Anti-Malarial Activity, Toxicological Effect, Traditional Medicine DOI: 10.7176/JNSR/12-22-04 Publication date: November 30 th 2021

Comparative in vivo antimalarial activities of aqueous and methanol extracts of MAMA powder - A herbal antimalarial preparation

Ethnopharmacological relevanceThe choice of extraction solvent is a significant consideration in ethnomedicine as optimal extraction could influence the bioactivity of the herbal medicinal product. Aim of studyThis study investigated the possible influence of the choice of solvents (methanol and water) for extracting MAMA Powder (MP) against Plasmodium berghei-infected mice to optimize its antimalarial activity and for developing other pharmaceutical dosage forms. Materials and methodsAqueous and methanol extracts of MP, obtained through the decoction and soxhlet methods, respectively, were subjected to liquid chromatography-mass spectroscopy (LC-MS) for their respective fingerprints. The antimalarial activities of the methanol and aqueous extracts (12.5–100 mg/kg) were evaluated orally using the chemosuppressive test model on chloroquine-sensitive Plasmodium berghei-infected mice. The methanol extract was subjected to the established infection and prophylactic antimalarial tests with chloroquine (10 mg/kg) and pyrimethamine (1.25 mg/kg) as positive controls, respectively. The aqueous extract was investigated in chloroquine-resistant P. berghei using the chemosuppressive (12.5–800 mg/kg) and established infection (25–400 mg/kg) antimalarial models. ResultsThe LC-MS fingerprints of both aqueous and methanol extracts revealed similar indole alkaloid contents. Chemosuppressive activity of the aqueous extract (75.3%) was significantly (p < 0.05) higher than the methanol extract (67.6%). In the chloroquine-resistant P. berghei infection experiments, the aqueous extract (400 mg/kg) exhibited significant parasite clearance (72%). ConclusionThe study concluded that the water extract with higher antimalarial activity could be optimized for chloroquine-resistant malaria and can thus facilitate the production of liquid and solid dosage forms.