Chloroquine-resistant Strains Of Plasmodium Falciparum Research Articles

Towards development of new antimalarial compounds through in silico and in vitro assays

Malaria is one of most widespread infectious disease in world. The antimalarial therapy presents a series of limitations, such as toxicity and the emergence of resistance, which makes the search for new drugs urgent. Thus, it becomes necessary to explore essential and exclusive therapeutic targets of the parasite to achieve selective inhibition. Enoyl-ACP reductase is an enzyme of the type II fatty acid biosynthetic pathway and is responsible for the rate-limiting step in the fatty acid elongation cycle. In this work, we use hierarchical virtual screening and drug repositioning strategies to prioritize compounds for phenotypic assays and molecular dynamics studies. The molecules were tested against chloroquine-resistant W2 strain of Plasmodium falciparum (EC50 between 330.05 and 13.92 µM). Nitrofurantoin was the best antimalarial activity at low micromolar range (EC50 = 13.92 µM). However, a hit compound against malaria must have a biological activity value below 1 µM. A large number of molecules present problems with permeability in biological membranes and reaching an effective concentration in their target's microenvironment. Nitrofurantoin derivatives with inclusions of groups which confer increased lipid solubility (methyl groups, halogens and substituted and unsubstituted aromatic rings) have been proposed. These derivatives were pulled through the lipid bilayer in molecular dynamics simulations. Molecules 14, 18 and 21 presented lower free energy values than nitrofurantoin when crossing the lipid bilayer.

Evaluation of antiplasmodial potential of Cissampelos pareira L.: Characterization and quantification of isoquinoline alkaloids responsible for the biological activity

Globally, based on traditional knowledge, different parts of Cissampelos pareira plant are being used individually or in combination in various forms to manage malaria. However, the scientific investigation for validating the most effective part of this plant against malaria parasite has not been done. Thus, the study aims to explore the antiplasmodial potential of different parts of the plant against malaria parasite by bio-assay guided isolation of compounds from different extracts and fractions. Antiplasmodial activities of the whole plant parent extract and its fractions along with decoctions (roots, stem, leaves and whole plant) and isolated molecules were evaluated against chloroquine-sensitive Pf3D7 and chloroquine-resistant PfINDO strains of Plasmodium falciparum. A UPLC-DAD based method was developed to quantify the marker compounds in all samples by utilizing isolated molecules as analytical standards. The chloroform fraction of the whole plant was found to be the most potent with IC50 (µg/mL) of 0.79 (Pf3D7) and 2.26 (PfINDO) followed by root decoction with IC50 (µg/mL) 10.22 (Pf3D7) and 7.7 (PfINDO). Further, phytochemical analysis of active chloroform fraction led to the isolation of two potent bisbenzylisoquinoline compounds, namely O,O-dimethylcurine (1) [IC50 (µM) 1.46 (Pf3D7) and 0.51 (PfINDO)], and curine (2) [IC50 (µM) 1.46 (Pf3D7) and 0.51 (PfINDO)]. Analysis of developed UPLC-DAD method showed the highest quantities of curine (2) (∼107 mg/g) and O,O-dimethylcurine (1) (∼15 mg/g) in chloroform fraction which might be responsible for its potent activity. This study showed that the root decoction was more effective than decoctions of each of the other parts of the plant and the whole plant hydroalcoholic extract.

New antimalarial iromycin analogs produced by Streptomyces sp. RBL-0292.

Two new antimalarial compounds, named prenylpyridones A (1) and B (2), were discovered from the actinomycete cultured material of Streptomyces sp. RBL-0292 isolated from the soil on Hamahiga Island in Okinawa prefecture. The structures of 1 and 2 were elucidated as new iromycin analogs having α-pyridone ring by MS and NMR analyses. Compounds 1 and 2 showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 80.7 to 106.7 µM.

Akedanones A-C, In Vitro and In Vivo Antiplasmodial 2,3-Dihydronaphthoquinones Produced by Streptomyces sp. K20-0187.

Three new antiplasmodial compounds, named akedanones A (1), B (2), and C (3), were discovered from the cultured material of Streptomyces sp. K20-0187 isolated from a soil sample collected at Takeda, Kofu, Yamanashi prefecture in Japan. The structures of compounds 1-3 were elucidated as new 2,3-dihydronaphthoquinones having prenyl and reverse prenyl groups by mass spectrometry and nuclear magnetic resonance analyses. Compound 1 and the known furanonaphthoquinone I (4) showed potent in vitro antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with half-maximal inhibitory concentration values ranging from 0.06 to 0.3 μM. Compounds 1 and 4 also displayed potent in vivo antiplasmodial activity against drug-sensitive rodent malaria Plasmodium berghei N strain, with inhibition rates of 47.6 and 43.1%, respectively, on intraperitoneal administration at a dose of 5 mg kg-1 day-1 for 4 days.

Phytochemical profiling of Striga asiatica; characterisation and anti-microbial assessment of the isolates

One undescribed compound, striasinol (1), and twelve previously described compounds were isolated from the aerial parts of Striga asiatica. Structure elucidation of isolated compounds was achieved by the interpretation of 1D and 2D NMR and HRESIMS data. The absolute configuration (1S,5S) of 1 was ascertained based on GIAO NMR calculations, DP4+ probability analysis, and a comparison of the experimental and calculated specific rotation values. The isolated compounds were evaluated for their antimalarial action, and none was found to be effective against the chloroquine-sensitive (D6) or chloroquine-resistant (W2) strains of Plasmodium falciparum. The isolates were found non-toxic to the Vero cell line as well. Subsequent testing of these metabolites for antimicrobial activities against various bacterial and fungal strains (up to 20 µg/mL), revealed that compounds 6 (chryseriol) and 7 (apigenin) showed a reasonable activity towards methicillin-resistant Staphylococcus aureus ATCC 1708 (MRSA), with IC50 values of 5.81 and 3.60 μg/mL, respectively.

N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum.

Antimalarial resistance has hampered the effective treatment of malaria, a parasitic disease caused by Plasmodium species. As part of our campaign on phenotypic screening of phenylhydrazones, a library of six phenylhydrazones was reconstructed and evaluated for their in vitro antimalarial and in silico receptor binding and pharmacokinetic properties. The structures of the phenylhydrazone hybrids were largely confirmed using nuclear magnetic resonance techniques. We identified two compounds which exhibited significant antimalarial potential against the ring stage (trophozoite) of 3D7 chloroquine-sensitive (CS) strain and DD2 chloroquine-resistant (CR) strains of Plasmodium falciparum with monosubstituted analogs bearing meta or para electron-donating groups showing significant activity in the single-digit micromolar range. Structure activity relationship is presented showing that electron-donating groups on the substituent hydrophobic pharmacophore are required for antimalarial activity. Compounds PHN6 and PHN3 were found to be the most potent with pIC50s (calculated form in vitro IC50s) of 5.37 and 5.18 against 3D7 CS and DD2 CR strains, respectively. Our selected ligands (PHN3 and PHN6) performed better when compared to chloroquine regarding binding affinity and molecular stability with the regulatory proteins of Plasmodium falciparum, hence predicted to be largely responsible for their in vitro activity. Pharmacokinetic prediction demonstrated that the phenylhydrazones may not cross the blood-brain barrier and are not P-glycoprotein (P-gp) substrates, a good absorption of 62% to 69%, and classified as a category IV compound based on toxicity grading.

In vitro antiplasmodial activity, LC-MS analysis, and molecular docking studies of bioactive compounds from Tetrapleura tetraptera (Fabaceae) fruits

Malaria continues to be a major public health concern, particularly for children and pregnant women in areas where the disease is endemic. Developing safe and efficient antimalarial therapies to fight the disease is essential. Medicinal plants represent a potential source for the development of new antimalarial drugs. Tetrapleura tetraptera is a plant native to West Africa and traditionally used to treat several diseases including Malaria. Here, we investigated the antiplasmodial activities of T. tetraptera fruit extracts against the chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfDD2) strains of Plasmodium falciparum in vitro using SYBR green assay. In addition, the antioxidant potential of the fruit extracts was also determined. LC-MS analysis was carried out to identify the bioactive compounds in the extracts. Molecular docking studies provide significant prima facie evidence of inhibition hence, to evaluate the potential inhibition of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a validated malaria drug target, the identified compounds were docked against PfDHODH. Strong antiplasmodial activities were demonstrated by the ethyl acetate and ethanolic extracts of T. tetraptera fruit, with IC50 values of 16.12 ± 0.04 µg/mL and 2.06 ± 0.02 µg/mL against the Pf3D7 strain, respectively. In the DPPH radical scavenging experiment, the ethanolic extract revealed considerable antioxidant activity with an EC50 value of 0.21 ± 0.82 mg/mL. Seven bioactive compounds were identified in the extract using LC-MS analysis. N-Methyl-1H-indole-3-propanamide (I), Tazolol (II), and Isopentyl salicylate (III) were identified as potential inhibitors of PfDHODH with high binding affinities ranging from -32.08 to -30.69 kcal/mol. The potential lead compounds also interacted with Gly181, Leu531, and Arg265, which are critical amino acid residues in the catalytic activity of PfDHODH. These findings support the traditional use of T. tetraptera fruit extracts for the treatment of malaria and as promising avenues for antimalarial drug development.

Antiplasmodial and cytotoxic activities of selected medicinal plants in Western Kenya

Malaria is a potentially lethal illness that is transmitted through the bite of mosquitoes and is caused by a parasitic organism. Individuals who are pregnant, small children, and the elderly are considered to be especially susceptible to the condition. The presently accessible antimalarial medications are associated with adverse effects and substantial expenses, particularly in regions with little financial resources. Medicinal plants present a viable option owing to their reduced incidence of adverse effects, decreased financial burden, and convenient availability. Nevertheless, the existing body of research pertaining to the utilization of medicinal plants for the treatment of malaria is somewhat restricted. The objective of this study was to investigate the cytotoxic and antiplasmodial characteristics of various medicinal plants found in Kakamega County, located in Western Kenya. In vitro studies were conducted using organic and aqueous extracts derived from the plants. The extracts were used to assess both chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Additionally, an evaluation was conducted to determine the safety and cytotoxicity of the plant extracts. The plant extracts obtained from dichloromethane exhibited the lowest yield, whereas the water extracts yielded the highest proportion. Plants belonging to the Leguminosae family, namely Senna didmobotrya and Senna occidentalis, exhibited the most substantial productivity when subjected to water and methanol solvents. Several plant extracts shown significant antiplasmodial action against both the chloroquine-sensitive and chloroquine-resistant strains of the malaria parasite. A number of extracts had a moderate level of antiplasmodial action, but a small subset exhibited poor or negligible activity. Of the three examined extract types (water, methanol, and dichloromethane), it was shown that the methanol extracts exhibited the greatest prevalence of plants with significant antiplasmodial activity against the chloroquine-sensitive strain. The majority of the methanol extracts exhibited moderate action against both strains, although a minority shown low or no activity. The extracts of dichloromethane also exhibited a variety of antiplasmodial properties. In general, the study unveiled the therapeutic potential of medicinal plants found in Kakamega County, located in Western Kenya, for the treatment of malaria. The efficacy of these plants in inhibiting the growth of both chloroquine-sensitive and chloroquine-resistant strains of the malaria parasite was demonstrated. The results of this study offer significant insights for stakeholders who are interested in investigating the potential of herbal remedies as an alternate strategy for the treatment of malaria.

In vitro Antiplasmodial, Antioxidant, and Cytotoxicity Activity of Terminalia macroptera Traditionally Used in Cameroon Against Malaria

BackgroundThe alarming expansion of drug resistance, as well as the scarcity of effective antimalarial medications currently accessible, highlights the importance of finding novel antimalarial chemicals. This study was undertaken to evaluate the antiplasmodial efficacy, antioxidant, and cytotoxicity of Terminalia macroptera stem bark in order to justify it as an antimalarial agent for the local population. MethodologyAqueous and ethanol extracts of the stem bark were prepared using standard procedures. The antimalarial activity of the plant extract was investigated in culture using the fluorescence-based SYBR Green assay against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. The antioxidant activity was determined by measuring ferric reducing antioxidant power, 1,1-diphenyl-2-picrylhydrazyl, free radical scavenging, and nitric oxide radical scavenging. Cytotoxicity of the extracts was conducted against RAW 264.7 cell line and red blood cells. ResultsThe aqueous and ethanolic extracts of T macroptera were active with inhibitory concentration 50 (IC50) for 3D7 strains of 3.46 ± 0.48 and 4.10 ± 0.39μg/ml for the aqueous and ethanolic extracts, respectively. The same activity was obtained with the Dd2 strain with IC50 of 6.15 ± 1.46 and 7.47 ± 0.03μg/ml for the aqueous and ethanolic extracts, respectively. The aqueous extracts showed good free radical scavenging property. The IC50 of the aqueous extract was found to be 0.87, 8.49, 72.78, and 25.92μg/ml for 1,1-diphenyl-2-picrylhydrazyl, nitric oxide, H2O2, and ferric reducing antioxidant power, respectively. For the cytotoxicity test, aqueous and ethanolic extracts of T macroptera were non-toxic with a CC50 value of 292.55 ± 1.35 and 223.25 ± 2.75 µg/ml for ethanolic and aqueous, respectively. Regarding the cytotoxicity of the extracts on red blood cells (haemolysis), the two extracts showed very low toxicity compared to the positive control. Phytochemical screening of the plants extract revealed the presence of alkaloids, triterpenoids, anthocyanins, anthraquinons, saponins, flavonoids, and phenolics. ConclusionsThese findings suggest that extracts of T macroptera can serve as antimalarial agents. Further in vivo, antimalarial, antioxidant, and toxicity studies are required to scientifically validate the use of T macroptera as an antimalarial agent.

Ferrocene-Based Drugs, Delivery Nanomaterials and Fenton Mechanism: State of the Art, Recent Developments and Prospects.

Ferrocene has been the most used organometallic moiety introduced in organic and bioinorganic drugs to cure cancers and various other diseases. Following several pioneering studies, two real breakthroughs occurred in 1996 and 1997. In 1996, Jaouen et al. reported ferrocifens, ferrocene analogs of tamoxifen, the chemotherapeutic for hormone-dependent breast cancer. Several ferrocifens are now in preclinical evaluation. Independently, in 1997, ferroquine, an analog of the antimalarial drug chloroquine upon the introduction of a ferrocenyl substituent in the carbon chain, was reported by the Biot-Brocard group and found to be active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Ferroquine, in combination with artefenomel, completed phase IIb clinical evaluation in 2019. More than 1000 studies have been published on ferrocenyl-containing pharmacophores against infectious diseases, including parasitic, bacterial, fungal, and viral infections, but the relationship between structure and biological activity has been scarcely demonstrated, unlike for ferrocifens and ferroquines. In a majority of ferrocene-containing drugs, however, the production of reactive oxygen species (ROS), in particular the OH. radical, produced by Fenton catalysis, plays a key role and is scrutinized in this mini-review, together with the supramolecular approach utilizing drug delivery nanosystems, such as micelles, metal-organic frameworks (MOFs), polymers, and dendrimers.

Palladium-catalyzed facile synthesis of imidazo[1,2-a]pyridine-flavone hybrids and evaluation of their antiplasmodial activity

An efficient cross-coupling reaction between imidazo[1,2-a]pyridine derivatives and 6-bromoflavones has been well established. This reaction proceeds through a Palladium-catalyzed cross-coupling reaction to provide imidazo[1,2-a]pyridine-flavone hybrids in good to excellent yield. Short reaction time, high yield, and wide substrate scope are the major advantages of this method. Using SYBR Green I assay, these hybrid molecules were examined for anti-plasmodial activity against Chloroquine-sensitive 3D7 and Chloroquine-resistant K1 strains of Plasmodium falciparum. The compounds 9o {IC50s (µM) 1.983D7, 1.98K1} and 9p {IC50s (µM) 1.923D7, 5.45K1} were found to be the most potent anti-plasmodial compounds in the series. Also, all these compounds were found to be non-cytotoxic towards Vero cells with their CC50s > 100 µM. We have conducted microscopic examination experiments on compounds 9o and 9p, which resulted in a drastic impact on parasite growth of the malaria parasite. The interaction of these two potent hybrids was also examined in the binding site of wild-type Pf-DHFR-TS (Plasmodium falciparum dihydrofolate reductase-thymidylate synthase) using molecular docking studies. The computational ADME studies of the hybrid compounds confirmed their significant physicochemical, pharmacokinetic, and drug-likeness properties confirming these hybrids as a new oral antimalarial agent. As a result, these new hybrid compounds could be valuable in the creation of future antimalarial drugs.

New antimalarial fusarochromanone analogs produced by the fungal strain Fusarium sp. FKI-9521.

Two new antimalarial compounds, named deacetyl fusarochromene (1) and 4'-O-acetyl fusarochromanone (2), were discovered from the static fungal cultured material of Fusarium sp. FKI-9521 isolated from feces of a stick insect (Ramulus mikado) together with three known compounds fusarochromanone (3), 3'-N-acetyl fusarochromanone (4), and 5 (fusarochromene or banchromene). The structures of 1 and 2 were elucidated as new analogs of 3 by MS and NMR analyses. The absolute configurations of 1, 2, and 4 were determined by chemical derivatization. All five compounds showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 0.08 to 6.35 µM.

Rubia cordifolia L. Crude Aerial Part Extracts Show a High Potential as Antimalarials against Chloroquine Resistant Plasmodium falciparum Strains in vitro

Pharmacognosy Research,2023,15,2,288-296.DOI:10.5530/pres.15.2.031Published:February 2023Type:Original Article Authors:Magara Jeremiah, Lucy Kamau, Grace Nyambati, and Hastings Ozwara Author(s) affiliations:Magara Jeremiah1, Lucy Kamau1, 2,*, Grace Nyambati3, Hastings Ozwara4 1Department of Zoological Sciences, Kenyatta University, Nairobi, KENYA. 2Department of Animal Sciences, Kenyatta University, Nairobi, KENYA. 3Department of Biomedical Sciences and Technology, The Technical University of Kenya, Nairobi, KENYA. 4Department of Tropical and Infectious Diseases, Institute of Primate Research, Nairobi, KENYA. Abstract:Introduction: Plasmodium falciparum human malaria parasite is resistant to most available medicines in Africa, necessitating research for new drugs. Rubia cordifolia L. is used in traditional malaria treatment in Kenya despite no supporting scientific data. Objectives: To evaluate anti-plasmodial efficacy of extracts from the aerial part of Rubia cordifolia against chloroquine sensitive (3D7) and resistant (W2) Plasmodium falciparum strains. Methods: Hexane, methanol and water were separately used in crude extractions from open shade dried aerial plant parts. Phytochemical composition was determined qualitatively. Anti-plasmodial efficacy of serial dilutions (range; 0.4 to 50 μg/ml) of each extract were evaluated in vitro and compared using ANOVA and Tukey’s HSD test, at p<0.05). Results: All the extracts significantly inhibited parasites growth, in a dose dependent manner. At 50 μg/ml, inhibition was (84.07%, 77.94% and 66.08%) for hexane, methanol and water extracts respectively against W2 and (80.06%, 78.36% and 60.92%) against 3D7 strain. Hexane extract showed IC50 0.551 μg/ml and 2.747 micrograms/ml against W2 and 3D7 respectively. Methanol extract, IC50 1.231 and 3.528 μ g/ml respectively, aqueous extract showed moderate activity, IC50 5.348 μg/ml and 17.341 μg/ml against the strains respectively. Chloroquine resistant (W2 strain) was more responsive to the extracts than 3D7 strain. Conclusion: Anti-plasmodial activities were in the order, Hexane>methanol>aqueous and were attributed to the phytochemicals present in the extracts. This presents evidence of R. cordifolia as anti-malarial drugs’ source. Further work is required to identify, purify, and characterize active molecules for development of anti-malaria drugs. Keywords:Antimalarial activity, Crude extracts, in vitro, Plasmodium falciparum, Rubia cordifolia.View:PDF (236.96 KB)

Antimalarial and Cytotoxic Activity of Native Plants Used in Cabo Verde Traditional Medicine.

Medicinal plants have historically been a source of drugs in multiple applications, including the treatment of malaria infections. The Cabo Verde archipelago harbors a rich diversity of native plants, most of which are used for medicinal purposes. The present study investigated the in vitro antiplasmodial activities of four native plants from Cabo Verde (i.e., Artemisia gorgonum, Lavandula rotundifolia, Sideroxylon marginatum, and Tamarix senegalensis). Traditional preparations of these medicinal plants, namely aqueous extracts (infusions) and ethanolic extracts, were tested against both chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains using the SYBR Green detection method. The in vitro cytotoxicity was evaluated in Caco-2 and PLP2 cells using a sulforhodamine B colorimetric assay. An ethanolic extract of A. gorgonum and infusions of T. senegalensis exhibited high antiplasmodial activities (EC50 < 5 μg/mL) without cytotoxicity (GI50 > 400 μg/mL). Extracts of L. rotundifolia and S. marginatum exhibited moderate activities, with EC50 values ranging from 10-30 μg/mL. The A. gorgonum ethanolic extract showed activity toward early ring stages, and parasites treated with the T. senegalensis infusions progressed to the early trophozoite stage, although did not develop further to the late trophozoite or schizont stages. Antimalarial activities and the lack of cytotoxicity of the extracts are reported in the present study and support previous claims by traditional practitioners for the use of these plants against malaria while suggesting their ethnopharmacological usefulness as future antimalarials.

Antiplasmodial activity of coumarins isolated from Polygala boliviensis: in vitro and in silico studies

Polygala boliviensis is found in the Brazilian semiarid region. This specie is little chemically and biologically studied. Polygala spp. have different metabolites, especially coumarins. Studies indicate that coumarins have antimalarial potential, denoting the importance of researching new active compounds from plants, since the resistance of Plasmodium strains to conventional therapy has increased. The present study aimed to evaluate the antiplasmodial activity of auraptene and poligalen against a chloroquine-resistant strain of Plasmodium falciparum. Coumarins were isolated from P. boliviensis by open column chromatography and identified by Nuclear Magnetic Resonance Spectroscopy. A cytotoxicity assay was carried out using MTT test, and the in vitro antiplasmodial activity was evaluated using the W2 strain. The antiplasmodial activity results found were IC50=0.171 ± 0.016 for auraptene and 0.164 ± 0.012 for poligalen; the selectivity indexes were 78.71 and 609.76, respectively. Inverse virtual screening in the BRAMMT database by OCTOPUS 1.2 was applied to coumarins to find potential P. falciparum targets and showed higher affinity energy of auraptene for purine nucleoside phosphorylase (PfPNP) and of poligalen for dihydroorotate dehydrogenase (PfDHODH). Molecular Dynamics studies (MD and MM-GBSA) approach were applied to calculate binding energies against selected P. falciparum targets and showed that all coumarins were stable at the binding site during simulations. Furthermore, energies were favorable for complexation. This is the first report of auraptene in P. boliviensis species and of in vitro antiplasmodial activity of auraptene and poligalen. In silico studies indicated that the mechanism of action of coumarins is the inhibition of PfPNP and PfDHODH. Communicated by Ramaswamy H. Sarma

Ultrasound-assisted-one-pot synthesis and antiplasmodium evaluation of 3-substituted-isoindolin-1-ones.

As the attempts to control malaria through chemotherapy strategies are restricted, we have prepared a small library of 3-substituted-isoindolinones from (Z)-3-benzylideneisobenzofuran-1(3H)-ones in one-pot fashion under ultrasound irradiation. The one-pot reaction was scalable and efficiently produced the desired products (1a-m) in high yields in a short reaction time. Evaluation of their in vitro antiplasmodium assay against the 3D7 (chloroquine-sensitive) and FCR3 (chloroquine-resistant) strains of Plasmodium falciparum demonstrated that they displayed moderate to strong antiplasmodium activities (the IC50 values ranging from 4.21-34.80 μM) and low resistance indices. The in silico prediction of ADME and physicochemical properties showed that the synthesized compounds met the drug-likeliness requirements and featured low toxicity effects. Based on the evaluation of the antiplasmodium profiles, 3-substituted-isoindolinone derivatives of 1a, 1d, 1h, and 1l may become potential antiplasmodium candidates.

Phytochemical investigation of Teucrium pruinosum and biological potential assessment of the isolated diterpenoids

Twenty-three compounds of diverse classes including iridoid glycosides (1–3), phenylethanoids (4 and 14), neo-clerodane diterpenoids (5–9), abietene diterpenoids (10–12), sesquiterpenoids (13), steroids (15), and flavonoids (16–23) were isolated from the whole plant Teucrium pruinosum. Their structures were determined by analysis of spectoscopic data. The diterpenoids (5–12) were tested for antimicrobial, antiplasmodial, and anti-inflammatory activities. 7-O-acetylhorminone (10) showed significant activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 values of 7.1 and 12.0 μM, respectively, and anti-inflammatory activity via iNOS inhibition with an IC50 value of 0.55 ± 0.07 μM. This is the first report regarding the chemical constituents and biological activities of T. pruinosum. The chemotaxonomic significance of the isolated compounds is discussed.

Chitosan-supported FeCl3 catalyzed multicomponent synthesis of tetrahydroisoquinoline-indole hybrids with promising activity against chloroquine resistant Plasmodium falciparum

An operationally simple three-component coupling of tetrahydroisoquinoline (THIQ), aldehydes and indoles or indole-3-carboxylic acids has been achieved using chitosan-ionic liquid supported FeCl3 (chit-IL@FeCl3) as a recyclable heterogeneous catalyst. The developed waste-free approach provided rapid access to biologically important THIQ-indole hybrids without the use of any additive or ligand. The synthesized THIQ-indole hybrids were evaluated as antiplasmodial agents against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of Plasmodium falciparum. Compounds 4b (most potent against Pf3D7) and 4g (most potent against PfINDO) showed IC50 values of 1.32 and 0.26 µg/mL respectively. Also, 4g showed strong cytocidal action against both rings and trophozoite stages. Furthermore, cytotoxic study against human liver HUH 7 cells revealed that the most potent compound 4g with an excellent resistance index of 0.07 is also relatively non-toxic. The results of this study suggest that THIQ-indole hybrids hold an enormous potential for developing new antimalarial agents with novel mechanism of action.

Antiplasmodial and cytotoxic activity of lanostane type triterpenoids isolated from Leplaea mayombensis

Leplaeric acid E 5 , leplazarin 6a and 21-epileplazarin 6b , three new 3,4- seco -lanostane type triterpenes have been isolated from the stem bark of Leplaea mayombensis (Pellegr.) Staner along with fourteen known compounds from the fruits and roots. Leplaeric acid E, leplazarin and 21-epileplazarin, 15-α-hydroxy-3,4- seco -lanosta-4(28),8,24-triene-3,21-dioic acid, mayomlactones A and B, lanosta-7,24-dien-3-one, leplaeric acid A, B and C were screened in vitro for antiplasmodial activity against chloroquine-sensitive ( Pf3D7 ) and chloroquine-resistant ( PfINDO ) strains of Plasmodium falciparum and for cytotoxicity against CAL-27, CaCo2, Skov-3, and HepG2 cells line . Three compounds including 15-α-hydroxy-3,4- seco -lanosta-4(28),8,24-triene-3,21-dioic acid (IC 50 5.65–7.09 μM), lanosta-7,24-dien-3-one (IC 50 7.18–9.07 μM), and leplaeric acid C (IC 50 7.59–8.47 μM) were the most active against both strains of P. falciparum . All the compounds exhibited cytotoxicity against the three-cell lines with IC 50 ranging from 12.30 to 181.88 μM. These results confirm the usage of the medicinal plant L. mayombensis for the management of malaria and suggest that further lead optimization studies on potent compounds identified from this study could lead to the identification of potential of lead molecules as scaffold for new antimalarial drug discovery. • Three new terpenes and fourteen known compounds were isolated from Leplaea mayombensis . • Compound 5, 6a and 6b are new 3,4-seco-lanostane type triterpenoids. • Antiplasmodial activity and cytotoxicity of all compounds were assessed in vitro . • Compounds 7, 14 and 17 exhibit antiplasmodial activity with IC50 < 10 µM and all the compounds exhibited cytotoxicity.

Antimalarial and Anticancer Activity Evaluation of Bridged Ozonides, Aminoperoxides, and Tetraoxanes.

Bridged aminoperoxides, for the first time, were investigated for the in vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P. falciparum. A cyclic voltammetry study of peroxides was performed, and most of the compounds did not show a direct correlation in oxidative capacity-activity. Peroxides were analyzed for ROS production to understand their mechanism of action. However, none of the compounds has an impact on ROS generation, suggesting that ozonides induce apoptosis in HepG2 cells through ROS-independent dysfunction pathway.