Resistant Strains Of Plasmodium Falciparum Research Articles

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update.

Global efforts to eradicate malaria are threatened by multiple factors, particularly the emergence of antimalarial drug resistant strains of Plasmodium falciparum. Heat shock proteins (HSPs), particularly P. falciparum HSPs (PfHSPs), represent promising drug targets due to their essential roles in parasite survival and virulence across the various life cycle stages. Despite structural similarities between human and malarial HSPs posing challenges, there is substantial evidence for subtle differences that could be exploited for selective drug targeting. This review provides an update on the potential of targeting various PfHSP families (particularly PfHSP40, PfHSP70, and PfHSP90) and their interactions within PfHSP complexes as a strategy to develop new antimalarial drugs. In addition, the need for a deeper understanding of the role of HSP complexes at the host-parasite interface is highlighted, especially heterologous partnerships between human and malarial HSPs, as this opens novel opportunities for targeting protein-protein interactions crucial for malaria parasite survival and pathogenesis.

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.

Formal synthesis of bastimolide A using a chiral Horner-Wittig reagent and a bifunctional aldehyde as key building blocks

The macrolide bastimolide A represents an attractive synthetic target due to its promising activity against resistant strains of the malaria pathogen plasmodium falciparum. We report a straightforward formal synthesis of bastimolide A using a Horner-Wittig reagent and an aldehyde derived from the same chiral-pool based intermediate as key building blocks.

SAR Guided Synthesis of Potent, Selective and Artemisinin Synergistic New Imidazole Derivatives with Promising In Vitro Antiplasmodial and In Vivo Antimalarial Activities

AbstractGuided by Structural Activity Relationship (SAR), a series of synthetic tri‐ and tetra‐substituted imidazoles were studied for in vitro antiplasmodial activities against erythrocytic stages of chloroquine sensitive and resistant strains of Plasmodium falciparum using SYBR green I assay. This led to the identification of three potent (IC50 μM) derivatives : Im2 (0.75), Im5 (0.75) and Im22 (0.5). These three lead molecules present unique structural features with a common molecular architecture. Thus, Im2 and Im22 have phenyl rings at positions 4 and 5 of imidazole ring along with n‐hexyl at N3 position, and differ in the C2 substituent (3‐cyclopentyloxy‐4‐methoxy phenyl for Im2) versus naphthyl for Im22. In contrast, positions 4 and 5 in Im5 have pyridyl rings, with unsubstituted N3. Further, curative antimalarial studies with Im2 and Im5 in a Plasmodium berghei (ANKA) infected mouse model of malaria, revealed an increase in average survival time to 28.6±4.2 and 27.4±4 days respectively, as compared to 20.2±2.3 days for untreated control mice. Results of in vitro combination (Im22+Artemisinin) with ΣFIC50: 0.34–0.79, indicated promising synergy and prospects for the use of Im22 as a new constituent in Artemisinin combination therapy (ACT).

In vitro and in silico guided identification of antimalarial phytoconstituent(s) in the root of Citrus maxima (Burm.) Merr

As a part of our continuous effort to find new therapeutic agents from natural sources, the hydroalcoholic (1:1) extract of Citrus maxima (Burm.) Merr. root was selected for the identification of possible antimalarial phytoconstituents. From the extract, three flavonoids including luteolin were isolated and evaluated for in vitro antimalarial activity against the chloroquine-sensitive (Pf3D7) and resistant (PfRKL-9) strains of Plasmodium falciparum. Among these, luteolin (CM3) showed the highest antimalarial activity with IC50 values of 2.315 ± 0.489 and 2.691 ± 0.454 µg/ml against the Pf3D7 and PfRKL-9 strains respectively. To assess the safety of luteolin (CM3), a cytotoxicity study against a normal human embryonic kidney cell line (HEK-293) was performed and the compound was found to be safe with a CC50 value of 222.3 ± 1.443 µg/ml. The docking study against 26 target proteins of P. falciparum revealed that luteolin (CM3) has a better binding affinity with two proteins, viz. P. falciparum lactate dehydrogenase (PfLDG) and P. falciparum enoyl-ACP reductase (PfEAR) in comparison to the co-crystallized ligands. Furthermore, the molecular dynamics simulation study of the protein-ligand complexes also supported the binding affinity and interactions of luteolin (CM3) at the active sites. Finally, the binding free energy calculation revealed that the luteolin formed a thermodynamically more stable complex with PfLDG (-50.955 ± 17.184 kJ/mol) than PfEAR (-24.856 ± 13.739 kJ/mol). Overall, in this study, we identified an antimalarial marker in the hydroalcoholic extract of C. maxima root which may act by inhibiting PfLDG. Communicated by Ramaswamy H. Sarma

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.

Evaluating phytochemical constituents and in-vitro antiplasmodial and antioxidant activities of Fadogiella stigmatoloba, Hygrophylla auriculata, Hylodesmum repandum, and Porphyrostemma chevalieri extracts

IntroductionFadogiella stigmatoloba, Hygrophylla auriculata, Hylodesmum repandum and Porphyrostemma chevalieri are used against malaria in traditional medicine in the Democratic Republic of the Congo (DRC). To evaluate their potential in the treatment of this disease, the in vitro antiplasmodial property of these four plants was evaluated. All experiments were conducted on methanolic extracts performed on selected organ parts of these plants. MethodsThe methanolic extracts, obtained by maceration, were firstly screened in vitro against the chloroquine sensitive (3D7) and resistant (W2) Plasmodium falciparum strains by the measurement of lactate dehydrogenase activity, and on human keratinocytes (HaCat) cells by the MTT assay to determine their selectivity indices (SI). Secondly, the antioxidant activity of the same extracts was evaluated using DPPH and FRAP assays. Finally, the presence of specific phytochemical constituents was evaluated using standard methods and tentatively identified by GC-MS. ResultsAn optimum antiplasmodial activity (IC50 = 3.4 ± 0.7 μg/mL, for 3D7, SI = 58.2; IC50 = 7 ± 1.0 μg/mL, for W2, SI = 28.3) was obtained with the leave extract of P. chevalieri. The leaves (for F. stigmatoloba and H. repandum), and the aerial part (for H. repandum) extracts showed promising and moderate antiplasmodial activities against respectively the 3D7 strain (IC50: <15 μg/mL), and W2 strain (IC50:15–50 μg/mL). All extracts presented a weak cytotoxic effect (IC50: >100 μg/mL) on HaCat cells. For the antioxidant test, the most interesting activity was obtained with the leaf extract of P. chevalieri. The GC–MS analysis of these four plants species extracts revealed the presence of various compounds, such as Ethyl 2-nonenoate, 2-(2-Hydroxy-2-phenylethyl)-3,5,6-trimethyl pyrazine, Palmitic Acid, Ethyl palmitate, Ethyl linolenate, and N-Acetyltyramine. ConclusionBased on the obtained results, P. chevalieri could be selected for further investigations or ⁄and for the management of malaria after standardization.

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.

Polyketide- and Terpenoid-Derived Metabolites Produced by a Marine-Derived Fungus, Peroneutypa sp.

Bioassay-guided investigation of the EtOAc-soluble extract of a culture of the marine-derived fungus Peroneutypa sp. M16 led to the isolation of seven new polyketide- and terpenoid-derived metabolites (1, 2, 4-8), along with known polyketides (3, 9-13). Structures of compounds 1, 2, and 4-8 were established by analysis of spectroscopic data. Absolute configurations of compounds 1, 2, 4, 6, 7, and 8 were determined by the comparison of experimental ECD spectra with calculated CD data. Compound 5 exhibited moderate antiplasmodial activity against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum.

Preliminary insight into the potential antiplasmodial activity and cytotoxicity of Bufo bufo and Incilius alvarius poison

The rise and spread of resistant Plasmodium falciparum strains are responsible for an increase in therapeutic failures in many of the regions endemic with malaria. The need for new therapeutic candidates is now more urgent than ever. Animal venoms have long been considered as interesting resources to exploit in terms of potential therapeutic candidates. Among these, the cutaneous secretions of toads constitute a rich and diverse source of bioactive molecules. We focused on two different species: Bufo bufo and Incilius alvarius. The dried secretions underwent a solvent-based extraction and were submitted to a systematic bio-guided fractionation approach using preparative thin-layer chromatography. Initial crude extracts were tested in vitro for their antiplasmodial activity. Based on these results, only crude extracts displaying IC50 < 100 μg/mL were considered for further fractionation. All extracts and fractions, including those that did not display antiplasmodial properties, were characterized by chromatographic (LC-UV/MS) and spectrometric techniques (HRMS). Antiplasmodial activity was evaluated in vitro using a chloroquine-sensitive strain (3D7) and a resistant one (W2). Toxicity was assessed on normal human cells for the samples displaying IC50 < 100 μg/mL. Crude extracts from Bufo bufo secretions exhibited no appreciable antiplasmodial activities. However, the methanol and dichloromethane extracts from Incilius alvarius secretions gave IC50 of (34 ± 4) μg/mL and (50 ± 1) μg/mL respectively when tested on W2 strain. No significant effect was observed on 3D7. This poison would warrant further investigation in terms of its antiplasmodial potential. Following preliminary characterization, it was revealed that the fractions of interest contained mainly bufotoxins, bufagins and alkaloids.

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)

Monitoring antimalarial drug-resistance markers in Somalia.

The use of an effective antimalarial drug is the cornerstone of malaria control. However, the development and spread of resistant Plasmodium falciparum strains have placed the global eradication of malaria in serious jeopardy. Molecular marker analysis constitutes the hallmark of the monitoring of Plasmodium drug-resistance. This study included 96 P. falciparum PCR-positive samples from southern Somalia. The P. falciparum chloroquine resistance transporter gene had high frequencies of K76T, A220S, Q271E, N326S, and R371I point mutations. The N86Y and Y184F mutant alleles of the P. falciparum multidrug resistance 1 gene were present in 84.7 and 62.4% of the isolates, respectively. No mutation was found in the P. falciparum Kelch-13 gene. This study revealed that chloroquine resistance markers are present at high frequencies, while the parasite remains sensitive to artemisinin (ART). The continuous monitoring of ART-resistant markers and in vitro susceptibility testing are strongly recommended to track resistant strains in real time.

Malaria outbreak in Laos caused by formerly rare artemisinin resistant strains of Plasmodium falciparum

In The Lancet Infectious Diseases, Varanya Wasakul and colleagues1 employed genomic analysis to characterise an outbreak of Plasmodium falciparum infections in Laos. They show that the outbreak was driven by an artemisinin resistant lineage that infiltrated the community in southern Laos during the 2020–21 malaria season, coinciding with a change in treatment policy in neighbouring countries.

Hitting drug-resistant malaria infection with triazole-linked flavonoid-chloroquine hybrid compounds.

Background: Malaria represents the major parasitic disease in tropical regions, and the development of new potent drugs is of pivotal importance. In this study, a series of hybrid molecules weredesigned by linking the 7-chloroquinoline core of chloroquine to different fluorinated flavonoid-related scaffolds. Materials & methods: Compounds were prepared by exploiting the click chemistry approach, allowing the introduction of a 1,2,3-triazole, a privileged structural motif in antiparasitic dug discovery. Results: Compounds 1b and 1c were the most interesting and were endowed with the highest in vitro activity, mainly against a resistant Plasmodium falciparum strain. They also inhibited hemozoin formation, and 1c was more effective than chloroquine against stage V gametocytes. Conclusion: The homoisoflavone core is a new, promising antimalarial scaffold that deserves further investigation.

Secondary metabolites of the leaves of Tricalysia atherura N. Hallé (Rubiaceae) and their potential antiplasmodial activity

One monoterpene indole alkaloid, atheruramine (1) bearing an ether bridge linking, one hydrobenzoin derivative, tricalydioloside (2) and two ursane-type triterpenes, atherurosides (A and B) (3 and 4) were isolated from the leaves of Tricalysia atherura, together with eight known compounds. The structures of these new compounds were elucidated on the basis of the results of spectroscopic analysis, and the relative configurations of compounds 1–3 were established by NOE difference. Four of the metabolites were screened in vitro against both chloroquine (CQ)-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum; they were found to exhibit moderate activity against chloroquine-resistant (Dd2) (IC50 64.99–92.29 μg/mL). Meanwhile, crude extract possesses high antiplasmodial activity against both 3D7 and Dd2 strains of P. falciparum (IC50 4.39–7.54 μg/mL) and high selectivity indices values (SI > 10) and was found to be safe.

Biological activities and physicochemical characterization of alkaline lignins obtained from branches and leaves of Buchenavia viridiflora with potential pharmaceutical and biomedical applications

In this work, we investigated in vitro different biological activities of alkaline lignins extracted from the species Buchenavia viridiflora, a tree from the Amazon rainforest used as a wood product. The chemical composition results for the twig and leaves were, respectively (%): cellulose (30.88 and 24. 28), hemicellulose (21.62 and 23.03), lignin (29.93 and 25.46), extractives (13.06 and 20.52), and ash (4.51 and 6.72). The yield was higher for the lignin of the branches (67.9 %) when compared to the leaves (60.2 %). Lignins are of the GSH type, low molecular weight and thermally stable. They promoted moderate to low antioxidant activity, highlighting the lignin of the branches, which presented an IC50 of 884.56 μg/mL for the DPPH assay and an IC50 of 14.08 μg/mL for ABTS. In the cytotoxicity assays, they showed low toxicity against macrophage cells (IC50 28.47 and 22.58 μg/mL). In addition, they were not cytotoxic against splenocytes and erythrocytes at concentrations ranging from 100 to 6.25 μg/mL. These were able to promote splenocyte proliferation and induce the production of anti-inflammatory cytokines. And inhibit the growth of tumor cells with IC50 ranging from 12.63 to values >100 μg/mL and microbial at a concentration of 512 μg/mL. Finally, they showed antiparasitic activity by inhibiting the growth of chloroquine-sensitive and resistant Plasmodium falciparum strains. These findings reinforce that the lignins in this study are promising for potential pharmaceutical and biomedical applications.

Indole alkaloid ellipticine as efficient multitarget compound

First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a five-step Cranwell and Saxton synthesis was used for obtaining ellipticine (Ell). Ellipticine hydrochloride salt (Ell×HCl) was also synthesized. Detailed in vitro studies of anticancer, antimalarial, and leishmanicidal activities were performed. Antiproliferation assay using DU145 cancer cell line treated with Ell showed a consistent reduction in cell proliferation and cell viability when treated with 5 μmol Ell. Anti-proliferation activity was more pronounced for the Ell×HCl solutions. Both the Ell and Ell×HCl revealed moderate activity in vitro against Leishmania amazonensis promastigotes, which is related to insufficient solubility of the drugs. IC50 values of Ell and Ell×HCl were determined in vitro against multidrug resistant Plasmodium falciparum strain K1. The Ell×HCl was shown to be almost three times more potent than the Ell in DMSO. Upon dilution with water, Ell solubility and activity drops down, while the activity and solubility of Ell×HCl is enhanced up to 10 times in 50:50 aqueous DMSO solutions

Rational Optimization of Dihydropyrimidinone-Quinoline Hybrids as Plasmodium falciparum Glutathione Reductase Inhibitors.

A series of dihydropyrimidinone-based antimalarial compounds were designed and synthesised based on the previously identified amide-based quinoline hybrids which showed good resistance reversal ability against the resistant strain of Plasmodium falciparum. The aromatic ring on the dihydropyrimidinone of the original hits was exchanged for a methyl group to bring the molecular weights below 500 Da and also determine the effect of the aromatic ring count on the resistance reversal ability of the hybrids. Apart from the previously used amide bond, the hybrid linker was also extended to the triazole linker. Although the triazole linker is synthetically easier to access, the use of an amide linker seems to have an activity advantage. The synthesised compounds in addition to the previously identified hits were subjected to molecular docking particularly targeting the orthosteric site of Plasmodium falciparum glutathione reductase (PfGR) protein. The ligand with the best binding interaction was rationally optimised to increase its suitability as a competitive inhibitor against the cofactor of the PfGR. Two of the optimised ligands showed better binding affinities than the cofactor while one of the two ligands displayed hydrophobically packed correlated hydrogen-bond which is very important in maintaining the ligand stability within the protein. In silico ADME predictions of the synthesised compounds indicate that these compounds possess good pharmacokinetic properties.

Quinoline-Dihydropyrimidin-2(1H)-one Hybrids: Synthesis, Biological Activity, and Mechanistic Studies.

A novel class of quinoline-dihydropyrimidin-2(1H)-one (DHPM) hybrids was synthesized and in vitro antiplasmodial activity was evaluated against chloroquine sensitive (D10) and chloroquine resistant (Dd2) strains of Plasmodium falciparum, the human malaria parasite. The antiplasmodial activity was compared to previously reported DHPM based molecular hybrids. Dual mode of antiplasmodial action of the most active member has been evaluated through heme binding study and in silico docking in the active site of dihydrofolate enzymes (wild-type as well as mutant). Favourable pharmacokinetic parameters were predicted in the ADMET evaluation. The new hybrids were also tested against a number of DNA and RNA viruses. No antiviral activity was found, except for one hybrid that showed mild inhibitory activity against two strains of cytomegalovirus (AD-169 and Davis), The most active hybrid was found to be a selective inhibitor of the growth of P. falciparum as well as a modest inhibitor of varicella zoster virus in HEL cells. Cytotoxicity of all hybrids was assessed in HEL, HeLa, Vero, MDCK, and CRFK cell cultures.

Synthesis and antimalarial activity of amide and ester conjugates of siderophores and ozonides.

Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides). All of the synthesized conjugates had potent antimalarial activities against the in vitro cultures of drug resistant and drug sensitive strains of Plasmodium falciparum. The work described herein provides the basis for future development of covalent combination of iron chelators and antimalarial chemotherapeutic agents for the treatment of cerebral malaria.