Chloroquine-sensitive 3D7 Research Articles

Structure and Biosynthesis of Perochalasins A-C, Open-Chain Merocytochalasans Produced by the Marine-Derived Fungus Peroneutypa sp. M16.

Novel open-chain merocytochalasans, perochalasins A-C (1-3), containing an unusual N-O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived Peroneutypa sp. M16 fungus, along with cytochalasin Z27 (4), cytochalasin Z28 (5), [12]-cytochalasin (6), and phenochalasin B (7). The structures of compounds 1-3 were established by analysis of the spectroscopic data. Full genome sequencing of Peroneutypa sp. M16 enabled the identification of a cytochalasan biosynthetic gene cluster and a proposal for the biosynthetic assembly of perochalasins. The proposal is supported by the nonenzymatic conversion of phenochalasin B (7) into 1-3, based on isotope-labeled hydroxylamine (15NH2OH and ND2OD) feeding studies in vivo and in vitro. In contrast to other merocytochalasans, these are the first cytochalasans confirmed to arise via nucleophilic addition and at a distinct location from the reactive macrocycle olefin, potentially expanding further the range of merocytochalasans to be discovered or engineered. Cytochalasin Z27 (4) exhibited antiplasmodial activities in the low micromolar range against the chloroquine-sensitive Plasmodium falciparum 3D7 strain as well as against resistant strains of the parasite (Dd2, TM90C6B, and 3D7r_MMV848).

Tetrahydropyridine appended 8-aminoquinoline derivatives: Design, synthesis, in silico, and in vitro antimalarial studies

Antimalarial drug resistance is a major obstacle in the ongoing quest against malaria. The disease affects half of the world’s population. The majority of them are toddlers and pregnant women. Needed a potent compound to act on drug-resistant Pf at appropriate concentrations without endangering the host. Envisaged solving this issue through rational drug design by creating a novel hybrid drug possessing two pharmacophores that can act on two marvellous and independent aims within the cell. Synthesized a new series of substituted 4-phenyl-1,2,3,6-tetrahydropyridine (THP) 8-Aminoquinoline-based hybrid analogs which have been integrated with quinoline, chloroquine, pamaquine, and primaquine, which exhibited antimalarial activity against Pf. Out of thirteen 4-phenyl-1,2,3,6-THP appended 8-Aminoquinoline derivatives, the compounds 1j, 1e, 1b, and 1l have exhibited good antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strain with the minimum inhibitory concentration. Compound 1b was the most effective and showed consistently good potency against the drug-resistant (RKL-9) strain, although all other arrays showed good antimalarial efficacy. Additional docking and molecular dynamics studies were carried out at several targeting sites to quantify the structural parameters necessary for the activity.

Design, in silico study, synthesis and evaluation of hybrid pyrazole substituted 1,3,5-triazine derivatives for antimalarial activity

ObjectivesMalaria is a significant global health challenge, particularly in Africa, Asia, and Latin America, necessitating immediate investigation into innovative and efficacious treatments. This work involves the development of pyrazole substituted 1,3,5-triazine derivatives as antimalarial agent. MethodsIn this study, ten compounds 7(a-j) were synthesized by using nucleophilic substitution reaction, screened for in silico study and their antimalarial activity were evaluated against 3D7 (chloroquine-sensitive) strain of P. falciparum. Key findingThe present work involves the development of hybrid trimethoxy pyrazole 1,3,5-triazine derivatives 7 (a–j). Through in silico analysis, four compounds were identified with favorable binding energy and dock scores. The primary focus of the docking investigations was on the examination of hydrogen bonding and the associated interactions with certain amino acid residues, including Arg A122, Ser A108, Ser A111, Ile A164, Asp A54, and Cys A15. The IC50 values of the four compounds were measured in vitro to assess their antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum. The IC50 values varied from 25.02 to 54.82 μg/mL. ConclusionAmong the ten derivatives, compound 7J has considerable potential as an antimalarial agent, making it a viable contender for further refinement in the realm of pharmaceutical exploration, with the aim of mitigating the global malaria load.

In vitro and in vivo antimalarial activities of the ethanol extract of Erythrina sigmoidea stem bark used for the treatment of malaria in the Western Region of Cameroon

BackgroundMalaria is one of the leading causes of morbidity and/or mortality in tropical Africa. The spread and development of resistance to chemical antimalarial drugs and the relatively high cost of the latter are problems associated with malaria control and are reasons to promote the use of plants to meet healthcare needs to treat malaria. The aim of this study was to evaluate antiplasmodial activities of extracts of Erythrina sigmoidea (Mah quat), which is traditionally used for the treatment of malaria in the western region of Cameroon.Material and methodsThe ethanol extract of E. sigmoidea stem bark was obtained through the maceration process using 95% ethanol, while the aqueous extract was prepared by infusion. The in vitro antiplasmodial effect of extracts against P. falciparum chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains was determined using the Trager and Jensen method. On the other hand, the in vivo antimalarial activity of the extract was evaluated in mice infected with Plasmodium berghei strain NK65 using the Peters’ 4-day suppressive test and Ryley test (curative test). A total of 36 mice were used, subdivided into six groups of six mice each: one normal control, a negative control, a positive control, and three other groups for the tested product. Blood samples were collected on the 10th day of each test for hematological parameters.ResultsThe aqueous extract had an in vitro antiplasmodial activity against the chloroquine-sensitive strain with an IC50 of 29.51 ± 3.63 µg/mL and against the chloroquine-resistant strain with an IC50 of 35.23 ± 3.17 µg/mL. The highest in vitro antiplasmodial activity was observed with the ethanol extract against the chloroquine-sensitive strain with an IC50 of 6.44 ± 0.08 µg/mL and against the chloroquine-resistant strain with an IC50 of 7.53 ± 0.22 µg/mL. The ethanol extract demonstrated suppressive activity in vivo with reduction rates of 87.69%, 86.79%, and 81.08% at doses of 500 mg/kg, 250 mg/kg, and 125 mg/kg, respectively; and curative activity in vivo with reduction rates of 80%, 78.5%, and 77.5% at doses of 500 mg/kg, 250 mg/kg, and 125 mg/kg, respectively. The number of white blood cells in the negative control (44.55 ± 5.02 103/µL) was higher compared to the other groups. As for the red blood cells, we observed a massive destruction of the latter in the infected and untreated group (5.82 ± 1.50 106/µL) compared to the infected and ethanol extract-treated groups (8.74 ± 1.57 106/µL for 500 mg/kg, 7.54 ± 1.77 106/µL for 250 mg/kg, and 8.9 ± 1.50 106/µL for 125 mg/kg).ConclusionThis study provides scientific data on the use of E. sigmoidea by the local population for the treatment of malaria. It shows that E. sigmoidea has antiplasmodial activity, and we also see that there are differences between the parameters that we have in the treated groups and those of the untreated group. However, toxicity tests are necessary to assess its safety.

Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice.

Antimalarial drugs are an urgently need and crucial tool in the campaign against malaria, which can threaten public health. In this study, we examined the cytotoxicity of the 9 antimalarial compounds chemically synthesized using SKM13-2HCl. Except for SKM13-2HCl, the 5 newly synthesized compounds had a 50% cytotoxic concentration (CC50) > 100 µM, indicating that they would be less cytotoxic than SKM13-2HCl. Among the 5 compounds, only SAM13-2HCl outperformed SKM13-2HCl for antimalarial activity, showing a 3- and 1.3-fold greater selective index (SI) (CC50/IC50) than SKM13-2HCl in vitro against both chloroquine-sensitive (3D7) and chloroquine -resistant (K1) Plasmodium falciparum strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious P. falciparum parasites. However, the antimalarial activity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound in the P. berghei NK65-infected mouse model, possibly because SAM13-2HCl had a lower polarity and less efficient pharmacokinetics than SKM13-2HCl. SAM13-2HCl was more toxic in the rodent model. Consequently, SAM13-2HCl containing morpholine was selected from screening a combination of pharmacologically significant structures as being the most effective in vitro against human-infectious P. falciparum but was less efficient in vivo in a P. berghei-infected animal model when compared with SKM13-2HCl. Therefore, SAM13-2HCl containing morpholine could be considered a promising compound to treat chloroquine-resistant P. falciparum infections, although further optimization is crucial to maintain antimalarial activity while reducing toxicity in animals.

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development of target-oriented molecules with novel modes of action. Given the importance of a plant-like Calcium-Dependent Protein Kinase 1 (PfCDPK1) as a stand-alone multistage signalling regulator of P. falciparum, we designed and synthesized 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a–s) and 9) directed towards PfCDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a ‘click’ reaction. The selected CQTrICh-analogs: 7l and 7r inhibited the growth of chloroquine-sensitive 3D7 strain and -resistant RKL-9 isolate of Plasmodium falciparum, with IC50 values of 2.4 μM &1.8 μM (7l), and 3.5 μM &2.7 μM (7r), respectively, and showed no apparent hemolytic activity and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. 7l and 7r were found to stably interact with the catalytically active ATP-binding pocket of PfCDPK1 via energetically favourable H-bonds. The interaction was confirmed in vitro by microscale thermophoresis and kinase assays, which demonstrated that the active hybrids interact with PfCDPK1 and inhibit its kinase activity which is presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating their selectivity for the parasite kinase. We report the antiplasmodial potential of novel kinase-targeting bio-conjugates, a step towards developing pan-kinase inhibitors which is a prerequisite for multistage anti-malarial protection.

Synthesis and Characterization of Phenylenediamine Side‐Chain‐Modified 4‐Aminoquinoline Mannich Bases and Evaluation of their in vitro Antimalarial Activity

AbstractTwelve novel compounds (Phenylenediamine side chain modified 4‐Aminoquinoline Mannich Bases) were synthesized and characterized by using a variety of analytical and spectroscopic methods. All the synthesized compounds were screened for in‐vitro antimalarial activity on 3D7 strain of Plasmodium falciparum. Synthesized compounds showed MIC values between 1.9 and 125 μg/ml in antimalarial screening (in‐vitro). Two compounds (MIC=1.9 μg/ml or 1.953 0.10 μM and 7.8 μg/ml or 2.200 0.08 μM) were found most potent against chloroquine sensitive 3D7 strain of Plasmodium falciparum which is comparable to standard drug chloroquine (MIC=0.4 μg/ml or 0.106 0.01 μM).

Hybrid PABA-glutamic acid conjugated 1,3,5-triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme.

Despite the successful reduction in the malaria health burden in recent years, it continues to remain a significant global health problem mainly because of the emerging resistance to first-line treatments. Also because of the disruption in malaria prevention services during the COVID-19 pandemic, there was an increase in malaria cases in 2021 compared to 2020. Hence, the present study outlined the in silico study, synthesis, and antimalarial evaluation of 1,3,5-triazine hybrids conjugated with PABA-glutamic acid. Docking study revealed higher binding energy compared to the originally bound ligand WR99210, predominant hydrogen bond interaction, and involvement of key amino acid residues, like Arg122, Ser120, and Arg59. Fourteen compounds were synthesized using traditional and microwave synthesis. The in vitro antimalarial evaluation against chloroquine-sensitive 3D7 and resistant Dd2 strain of Plasmodium falciparum showed a high to moderate activity range. Compounds C1 and B4 showed high efficacy against both strains and a further study revealed that compound C1 is non-cytotoxic against the HEK293 cell line with no acute oral toxicity. In vivo, study was performed for the most potent antimalarial compound C1 to optimize the research work and found to be effectively suppressing parasitemia of Plasmodium berghei strain in the Swiss albino mice model.

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.

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.

In vitro antiplasmodial activity and toxicological profile of extracts, fractions and chemical constituents of leaves and stem bark from Dacryodes edulis (Burseraceae)

BackgroundDacryodes edulis is a plant that belongs to the Burseraceae family. It is widely used traditionally alone or in association with other plants in Cameroonian folk medicine to cure wounds, fever, headaches, and malaria. The aim of this work was to investigate the leaves and stem bark of D. edulis with an emphasis on the antiplasmodial and cytotoxic effects of extracts, fractions, and isolated compounds.MethodsExtracts, fractions, and some isolated compounds were subjected to antiplasmodial activity screening in vitro against chloroquine-sensitive 3D7 and multidrug resistant Dd2 strains of Plasmodium falciparum using a SyBr Green fluorescence-based assay. The cytotoxicity of active extracts, fractions, and compounds was tested against mammalian Raw cell lines using an in vitro resazurin-based viability assay. The structures of the compounds were determined based on their NMR and MS data. The in vivo toxicity using female BALB/c mice was performed on the most active extract according to the protocol of OECD (2002), guideline 423.ResultsThe hydroethanolic extract from the leaves of D. edulis displayed good antiplasmodial activity with IC50 values of 3.10 and 3.56 μg/mL respectively on sensitive (3D7) and multiresistant (Dd2) strains of P. falciparum. Of the sixteen compounds isolated, 3,3′,4-tri-O-methylellagic acid (4) exhibited the highest antiplasmodial activity against PfDd2 strains with an IC50 value of 0.63 μg/mL. All extracts, fractions, and isolated compounds demonstrated no cytotoxicity against Raw cell lines with CC50 > 250 μg/mL. In addition, the most active extract on both strains of P. falciparum was nontoxic in vivo, with a LD50 greater than 2000 and 5000 mg/kg. A phytochemical investigation of the stem bark and leaves of D. edulis afforded sixteen compounds, including two xanthones (1–2), three ellagic acid derivatives (3–5), one phenolic compound (6), one depside (7), one triglyceride (8), one auranthiamide acetate (9), one gallic acid derivative (10), four triterpenoids (11–14), and two steroids (15–16). Compounds 1, 2, 5, 7, 8, and 9 were herein reported for the first time from the Burseraceae family.ConclusionThis work highlights the good in vitro antiplasmodial potency of the hydroethanolic extract of the leaves of this plant and that of two isolated constituents (3,3′,4-tri-O-methylellagic acid and ethylgallate) from the plant. These biological results support the use of D. edulis in traditional medicine against malaria.

In silico screening, synthesis, and antimalarial evaluation of PABA substituted 1,3,5-triazine derivatives as Pf-DHFR inhibitors

ObjectivesDrug resistance in malaria parasites necessitates the development of new antimalarial drugs with unique mechanisms of action. In the present research work, the PABA conjugated 1,3,5-triazine derivatives were designed as an antimalarial agent. MethodsIn this present work, a library of two hundred-seven compounds was prepared in twelve different series such as [4A (1-23), 4B(1-22), 4C(1-21), 4D(1-20), 4E(1-19), 4F(1-18), 4G(1-17), 4H(1-16), 4I(1-15), 4J(1-13), 4K(1-12) and 4L(1-11) ] respectively using different primary and secondary aliphatic and aromatic amines. Ten compounds were ultimately selected through in silico screening. They were synthesized by conventional and microwave-assisted methods followed by in vitro antimalarial evaluations performed in chloroquine-sensitive (3D7) and resistant (DD2) strains of P. falciparum. ResultsThe docking results showed that compound 4C(11) had good binding interaction with Phe116, Met55 (−464.70 kcal/mol) and Phe116, Ser111 (−432.60 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. Furthermore, in vitro, antimalarial activity results indicated that compound 4C(11) showed potent antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain of P. falciparum along with IC50 (14.90 μg mL−1) and (8.30 μg mL−1). ConclusionThese PABA-substituted 1,3,5-triazine compounds could be exploited to develop a new class of Pf-DHFR inhibitors as a lead candidate.

Ethanol Extracts from Selected Tanzanian Medicinal Plants Selectively Inhibit Plasmodium falciparum Growth In Vitro

This study aimed to assess the in vitro antiplasmodial and cytotoxic activities of ethanol extracts from the root barks, leaves and stem barks of seven medicinal plant species growing in Tanzania. The antiplasmodial activities of extracts against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) strains of Plasmodium falciparum were determined using a SYBR green I-based fluorescence assay, while the cytotoxicity of active extracts was determined against the human HepG2 cell line using a resazurin-based assay. Out of twenty-one extracts screened, two of them, namely, DFRE from Dracaena fragrans root bark (IC50Pf3D7 = 2.4 mg/mL) and EHSE from Erythrina haerdii stem bark (IC50Pf3D7 = 8.6 mg/mL and IC50PfDd2 = 7.6 mg/mL), exhibited good potencies against P. falciparum parasites. The two extracts emerged as the most promising and selective inhibitors (inhibited the growth of P. falciparum strains and were not toxic to the human HepG2 cell line) of chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) strains of P. falciparum. Eight other extracts showed moderate potencies with IC50 values ranging from 11–25 mg/mL against both plasmodial strains, while the remaining 11 extracts were mildly active with IC50 values ranging from 25.1 to 96.7 mg/mL. The results of the cytotoxicity test indicated that the median cytotoxic concentrations (CC50) of the tested extracts were all ≥ 224.8 mg/mL, leading to selectivity indices (SI) > 10-fold for most of the extracts. The findings described in this article support the traditional use of the investigated medicinal plants to treat malaria.
 Keywords: Antiplasmodial; Cytotoxicity; Ethanol extracts; Plasmodium falciparum

Antiplasmodial and Antioxidant Activity of Garcinia Bancana Extract

Malaria caused by Plasmodium parasites is a significant public health issue, particularly in tropical and subtropical regions. There is also resistance to chloroquine-based therapy, which highlights the need for novel therapeutic agents. Therefore, our project in exploring antiplasmodial agents from Garcinia Indonesia continues. This study evaluates the phytochemical content of G. bancana by the total phenolic content (TPC) and total flavonoid content (TFC) and its in vitro antioxidant and antiplasmodial activities. The TPC and TFC values were determined using a UV-VIS spectrophotometer, while the antioxidant activity was determined using the DPPH, ABTS, and FRAP assays. Antiplasmodial activity against a chloroquine-sensitive strain 3D7 was evaluated using the Giemsa staining method. The highest TPC value of 195.75 ± 1.24 mg GAE/g was obtained from methanolic extract, while a TFC value of 82.79 ± 0.34 mg QE/g extract was found from dichloromethane extract. The methanolic extract exhibited the most potent antioxidant activity in the DPPH and FRAP assays with IC50 values of 6.07 ± 0.06 μg/ml and 74.35 ± 3.77 μM Fe2+/g, respectively. The n-hexane extract was found to be the most potent on ABTS antioxidant and antiplasmodial assays with IC50 values of 1.22 ± 0.02 μg/ml and 0.23 ± 0.01 μg/ml, respectively. Furthermore, the DPPH antioxidant was negatively correlated with antiplasmodial significantly at 0.05. These findings suggest that the n-hexane extract of G. bancana has great potential as a source of antioxidant and antiplasmodial compounds. To the best of our knowledge, this study provides microscopic evidence in addition to the strongest antiplasmodial efficacy of Garcinia extract.

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.

In silico ADMET prediction, evaluation of cytotoxicity in mouse splenocytes and preliminary evaluation of in vitro antimalarial activity of 4-(4-chlorophenyl)thiazole compounds.

In this work, an in silico study and evaluation of the cytotoxicity of 4-(4-chlorophenyl)thiazole compounds against mouse splenocytes and the chloroquine-sensitive Plasmodium falciparum 3D7 strain are reported. The in silico results showed that the compounds have important pharmacokinetic properties for compounds with potential drug candidates. Regarding cytotoxicity assays against splenocytes, the compounds have low cytotoxicity. In addition, they were able to promote activation of these cells by increasing nitric oxide production without promoting cell death. Finally, they were able to promote cell proliferation. Regarding the in vitro anti-P. falciparum activity assays, it was observed that the compounds were able to inhibit the parasite's growth, presenting IC50 values ​​ranging from 0.79 to greater than 10 µM. These results are promising when compared to chloroquine. Therefore, this study showed that 4-(4-chlorophenyl)thiazole compounds are promising candidates for antimalarials.

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.

Substituted 3-styryl-2-pyrazoline Derivatives as an Antimalaria: Synthesis, in vitro Assay, Molecular Docking, Druglikeness Analysis and Admet Prediction

The synthesis, in vitro antimalarial assay, molecular docking, drug-likeness analysis, and ADMET prediction of substituted 3-styryl-2-pyrazoline derivatives as antimalaria have been conducted. The synthesis of N-phenyl (1a‒3a) and N-acetyl-substituted (1b‒3b) 3-styryl-2-pyrazolines was carried out using dibenzalacetone derivatives and hydrazine hydrate or phenylhydrazine. An in vitro antimalarial assay was conducted against the chloroquine-sensitive Plasmodium falciparum 3D7 strain, while molecular docking was performed toward the crystal protein of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) (PDB ID: 1J3I). Furthermore, the prediction of drug-like properties was determined by assessing Lipinski’s rules, and the pharmacokinetic parameters were also studied in-silico, including absorption, distribution, metabolism, excretion, and toxicity (ADMET). The in vitro assay showed that 3a (IC50 0.101 µM) has excellent antimalarial activity, followed by 2a (0.177 µM), and 1b (0.258 µM). Molecular docking has supported the in vitro assay by showing the lowest CDOCKER energy for 3a (‒56.316 kcal/mol), then 2a (‒51.2603 kcal/mol), and 1b (‒48.8774 kcal/mol). The drug-like properties showed that all of the prepared compounds were acceptable based on Lipinski’s rules and predicted to be potentially orally bioavailable. The ADMET analysis provided information that 3a and 2a could be proposed as the best lead antimalarial drugs with further modification to reduce the lipophilicity and toxicity properties.