Potential Antimalarial Compounds Research Articles

Molecular modeling studies on substituted aminopyrimidines derivatives as potential antimalarial compounds

We report combined study of k-nearest neighbor, pharmacophore and 2D QSAR was performed on a series of 2,4-diaminopyrimidines dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum as antimalarial agents to gain insights into the structural determinants and their structure–activity relationship. The QSAR models for the prediction of activity of antiplasmodial activities against P. falciparum clones with wild-type TM4/8.2 and K1CB1 strains have been developed by the SA-PLS and SW-PLS methods, and the proposed models gain satisfactory results. The statistically significant best 2D QSAR model having correlation coefficient r2 = 0.8569, 0.7853 and cross-validated squared correlation coefficient q2 = 0.7104, 0.7216 with external predictive ability of pred_r2 = 0.7995, 0.7064 was developed by wild-type TM4/8.2 and K1CB1 strains with SA-PLS. 3D QSAR studies using k-nearest neighbor molecular field analysis (kNN-MFA) method, identifies two models obtained by SA-PLS and SW-PLS methods leading to antimalarial activity prediction. The obtained pharmacophore model with lowest RMSD value (0.1548 A), consisting of one hydrogen donor, two hydrogen acceptors and one aromatic region was developed. These models were found to yield reliable clues for further optimization of 2,4-diaminopyrimidines derivatives in the data set. We hope that these results will give new insights into chemical modifications that can be realized with the aim of designing new inhibitors with improved pharmacological properties.

Synthesis, biological evaluation and molecular docking of novel chalcone–coumarin hybrids as anticancer and antimalarial agents

A new series of chalcone–coumarin derivatives (9–19) linked by the 1,2,3-triazole ring were synthesized through the azide/alkyne dipolar cycloaddition. Hybrid molecules were evaluated for their cytotoxic activity against four cancer cell lines (e.g., HuCCA-1, HepG2, A549 and MOLT-3) and antimalarial activity toward Plasmodium falciparum. Most of the synthesized hybrids, except for analogs 10 and 16, displayed cytotoxicity against MOLT-3 cell line without affecting normal cells. Analogs (10, 11, 16 and 18) exhibited higher inhibitory efficacy than the control drug, etoposide, in HepG2 cells. Significantly, the high cytotoxic potency of the hybrid 11 was shown to be non-toxic to normal cells. Interestingly, the chalcone–coumarin 18 was the most potent antimalarial compound affording IC50 value of 1.60 μM. Molecular docking suggested that the cytotoxicity of reported hybrids could be possibly due to their dual inhibition of α- and β-tubulins at GTP and colchicine binding sites, respectively. Furthermore, falcipain-2 was identified to be a plausible target site of the hybrids given their antimalarial potency.

Development of diaminoquinazoline histone lysine methyltransferase inhibitors as potent blood-stage antimalarial compounds.

Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1-benzyl-4-piperidyl)[6,7-dimethoxy-2-(4-methyl-1,4-diazepin-1-yl)-4-quinazolinyl]amine (BIX01294; 1), a known human G9a inhibitor, together with its dose-dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.

In silico analysis reveals the anti-malarial potential of quinolinyl chalcone derivatives

In this study, the correlation between chemical structures and various parameters such as steric effects and electrostatic interactions to the inhibitory activities of quinolinyl chalcone derivatives is derived to identify the key structural elements required in the rational design of potent and novel anti-malarial compounds. The molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are carried out on 38 chalcones derivatives using Plasmodium falciparum lactate dehydrogenase (PfLDH) as potential target. Surflex-dock is used to determine the probable binding conformations of all the compounds at the active site of pfLDH and to identify the hydrogen bonding interactions which could be used to alter the inhibitory activities. The CoMFA model has provided statistically significant results with the cross-validated correlation coefficient (q2) of .850 and the non-cross-validated correlation coefficient (r2) of .912. Standard error of estimation (SEE) is .280 and the optimum number of component is five. The predictive ability of the resultant model is evaluated using a test set comprising of 13 molecules and the predicted r2 value is .885. The results provide valuable insight for optimization of quinolinyl chalcone derivatives for better anti-malarial therapy.

ChemInform Abstract: New Route to the 5‐((Arylthio‐ and Heteroarylthio)methylene)‐3‐(2,2,2‐trifluoroethyl)‐furan‐2(5H)‐ones (II) —Key Intermediates in the Synthesis of 4‐Aminoquinoline γ‐Lactams (IV) as Potent Antimalarial Compounds.

AbstractMost new compounds (IV) exhibit good in vitro activity against P.

Synthesis and evaluation of antimalarial activity of curcumin derivatives

One of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC50 values ranging from 1.7 to 15.2 µg mL-1), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds.

Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-Stage Antimalarial Compounds

Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-Stage Antimalarial Compounds

Exploring Structural Requirements for a Class of Nucleoside Inhibitors (PfdUTPase) as Antimalarials: First Report on QSAR, Pharmacophore Mapping and Multiple Docking Studies

Multi-drug resistance to the available antimalarial drugs is a major threat for malaria treatment. Due to the recent characterization of human and parasite genome sequences, both ligand and target based drug design strategies may be helpful for the design of potential antimalarial compounds with reduced degree of resistance. The present work deals with quantitative structure-activity relationship (QSAR) modeling, pharmacophore mapping and docking studies of a series of 95 nucleoside analogs as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as a first line of defence against uracil incorporation into DNA. The QSAR and pharmacophore models were validated both internally and externally showing good statistical results. The docking study was performed and validated using three different software tools namely Discovery Studio 2.1 (Accelrys), Maestro 9.3 (Schrodinger) and MOE (Chemical Computing Group). The QSAR studies revealed that compounds containing substituted aromatic carbons (aasC fragment) and those bearing hydroxyl groups without an noxolane ring exert potent PfdUTPase inhibitory activity. The best pharmacophore hypothesis (hypothesis 1) possessed four features: (i) one hydrogen bond donor (HBD), (ii) one hydrogen bond acceptor (HBA), (iii) one hydrophobic (HYD) and (iv) one ring aromatic (RA). The docking studies revealed that the PfdUTPase inhibitors interact with a pocket containing Phe46, Lys48, Leu88, Asn103, Gly106, Leu107, Ile108, Tyr112, Ile116, Ile117, Ala118 and Ala119 amino acid residues. The interaction pattern of all the PfdUTPase inhibitors was almost same in case of docking using Discovery Studio 2.1, Maestro 9.3 and MOE software. This work thus presents the first QSAR report for nucleoside analogs which may serve as an efficient tool to address the increasing threat of malaria in the developing countries.

Antimalarial activity of nepodin isolated from Rumex crispus

The purpose of this study is to define the antimalarial activity of Rumex crispus. To identify an active compound that is isolated from R. crispus, bioassay-based chromatographic fractionation and purification is carried out from 70 % ethanol extract of R. crispus; then, an active compound, nepodin, is identified by spectroscopic analysis. Anitmalarial activity is measured by PfNDH2 assay, cytotoxicity, and animal test. From NADH:quinone oxidoreductase enzyme (PfNDAH2) assay, nepodin exhibited significant IC50 values that were 0.74 ± 0.07 and 0.79 ± 0.06 μg/ml against P. falciparum chloroquine-sensitive (3D7) and P. falciparum chloroquine-resistant (S20), respectively. Nepodin showed a potential selective inhibition (SI index: ratio of 50 % cytotoxic concentration to 50 % effective anti-plasmodial concentration) of 161.6 and 151.4 against P. falciparum 3D7 and P. falciparum S20. In the animal test, all groups of nepodin treatment of 10, 50, and 250 mg/kg were active with a parasitemia suppression of 97.1 ± 3.3, 99.1 ± 3.7, and 99.1 ± 2.6 %, respectively. The survival time with nepodin treatment was increased by 14.6 ± 2.5, 16.2 ± 1.5, and 19.8 ± 1.7 days at each dose, respectively. This study newly identified the plant R. crispus containing nepodin, which is a potential antimalarial compound. It exhibited the inhibitory activity of PfNDH2 and prolonged the survival time on the group of nepodin treatment; moreover, it inhibited the parasitemia in the animal test.

Discovery and preliminary structure–activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds

Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC50 0.89μM). Preliminary structure–activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC50 8.6nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics.

Phytochemical and Biological Activity Studies of the Bhutanese Medicinal Plant Corydalis crispa

The chemical constituents and biological activities of Corydalis crispa (Fumariaceae) were investigated for the first time. The phytochemical study resulted in the isolation of nine known isoquinoline alkaloids: protopine (1), 13-oxoprotopine (2), 13-oxocryptopine (3), stylopine (4), coreximine (5), rheagenine (6), ochrobirine (7), sibiricine (8) and bicuculline (9), with complete NMR data for 2 and 3 provided here for the first time. Crude extracts exhibitedsignificant anti-inflammatory (p < 0.01) activity against TNF-alpha production in LPS activated THP-1 cells. The acetylcholinesterase inhibitory activity of compounds 2, 4 and 7 and the antiplasmodial activity of compound 5 against P. falciparum strains TM4/8.2 and K1CB1 (multidrug resistant strain) are reported here for the first time. Stylopine (4) did not show antimalarial activity against the K1CB1 strain in contrast to a previous report. This study generated a scientific basis for the use of this plant in Bhutanese traditional medicine, either individually or in combination with other medicinal ingredients to treat a broad range of disorders. This study also identified compound 5 as potential new antimalarial lead compound.

Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes

Artemisinin, a sesquiterpene phytolactone derived from Artemisia annua, is a potent antimalarial compound with promising anticancer properties, although the mechanism of its anticancer signaling is not well understood. Artemisinin inhibited proliferation and induced a strong G1 cell cycle arrest of cultured MCF7 cells, an estrogen-responsive human breast cancer cell line that represents an early-stage cancer phenotype, and effectively inhibited the in-vivo growth of MCF7 cell-derived tumors from xenografts in athymic nude mice. Artemisinin also induced a growth arrest of tumorigenic human breast cancer cell lines with preneoplastic and late stage cancer phenotypes, but failed to arrest the growth of a nontumorigenic human mammary cell line. Concurrent with the cell cycle arrest of MCF7 cells, artemisinin selectively downregulated the transcript and protein levels of the CDK2 and CDK4 cyclin-dependent kinases, cyclin E, cyclin D1, and the E2F1 transcription factor. Analysis of CDK2 promoter-luciferase reporter constructs showed that the artemisinin ablation of CDK2 gene expression was accounted for by the loss of CDK2 promoter activity. Chromatin immunoprecipitation revealed that artemisinin inhibited E2F1 interactions with the endogenous MCF7 cell CDK2 and cyclin E promoters. Moreover, constitutive expression of exogenous E2F1 prevented the artemisinin-induced cell cycle arrest and downregulation of CDK2 and cyclin E gene expression. Taken together, our results demonstrate that the artemisinin disruption of E2F1 transcription factor expression mediates the cell cycle arrest of human breast cancer cells and represents a critical transcriptional pathway by which artemisinin controls human reproductive cancer cell growth.

Crystal structures of multidrug-resistant HIV-1 protease in complex with two potent anti-malarial compounds

Two potent inhibitors (compounds 1 and 2) of malarial aspartyl protease, plasmepsin-II, were evaluated against wild type (NL4-3) and multidrug-resistant clinical isolate 769 (MDR) variants of human immunodeficiency virus type-1 (HIV-1) aspartyl protease. Enzyme inhibition assays showed that both 1 and 2 have better potency against NL4-3 than against MDR protease. Crystal structures of MDR protease in complex with 1 and 2 were solved and analyzed. Crystallographic analysis revealed that the MDR protease exhibits a typical wide-open conformation of the flaps (Gly48 to Gly52) causing an overall expansion in the active site cavity, which, in turn caused unstable binding of the inhibitors. Due to the expansion of the active site cavity, both compounds showed loss of direct contacts with the MDR protease compared to the docking models of NL4-3. Multiple water molecules showed a rich network of hydrogen bonds contributing to the stability of the ligand binding in the distorted binding pockets of the MDR protease in both crystal structures. Docking analysis of 1 and 2 showed a decrease in the binding affinity for both compounds against MDR supporting our structure–function studies. Thus, compounds 1 and 2 show promising inhibitory activity against HIV-1 protease variants and hence are good candidates for further development to enhance their potency against NL4-3 as well as MDR HIV-1 protease variants.

Biological activities of nitidine, a potential anti-malarial lead compound

BackgroundNitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. The widespread use of these therapies stresses the importance of studying this molecule in the context of malaria control. However, little is known about its potential as an anti-plasmodial drug, as well as its mechanism of action.MethodsIn this study, the anti-malarial potential of nitidine was evaluated in vitro on CQ-sensitive and -resistant strains. The nitidine's selectivity index compared with cancerous and non-cancerous cell lines was then determined. In vivo assays were then performed, using the four-day Peter's test methodology. To gain information about nitidine's possible mode of action, its moment of action on the parasite cell cycle was studied, and its localization inside the parasite was determined using confocal microscopy. The in vitro abilities of nitidine to bind haem and to inhibit β-haematin formation were also demonstrated.ResultsNitidine showed similar in vitro activity in CQ-sensitive and resistant strains, and also a satisfying selectivity index (> 10) when compared with a non-cancerous cells line. Its in vivo activity was moderate; however, no sign of acute toxicity was observed during treatment. Nitidine's moment of action on the parasite cycle showed that it could not interfere with DNA replication; this was consistent with the observation that nitidine did not localize in the nucleus, but rather in the cytoplasm of the parasite. Nitidine was able to form a 1-1 complex with haem in vitro and also inhibited β-haematin formation with the same potency as chloroquine.ConclusionNitidine can be considered a potential anti-malarial lead compound. Its ability to complex haem and inhibit β-haematin formation suggests a mechanism of action similar to that of chloroquine. The anti-malarial activity of nitidine could therefore be improved by structural modification of this molecule to increase its penetration of the digestive vacuole in the parasite, where haemoglobin metabolization takes place.

Drug Screen Targeted at Plasmodium Liver Stages Identifies a Potent Multistage Antimalarial Drug

Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host’s liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo. Furthermore, decoquinate kills the parasite’s replicative blood stages and is active against developing gametocytes, the forms responsible for transmission. The drug acts by selectively and specifically inhibiting the parasite’s mitochondrial bc1 complex, with little cross-resistance with the antimalarial drug atovaquone. Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compound.

Theoretical Evaluation and Classifications of Potential Antimalarial Phenazine Compounds

This study demonstrates a methodology for evaluating the theoretical antimalarial potential of 18 phenazine derivatives, some of which have no known biological activities. Semi-empirical, density functional and statistical methods for analytical data treatment were used to establish a quantitative structure-activity relationship (QSAR). A set of 16 descriptors were obtained. Theoretical tools regarding inferential statistics were used to analyze and interpret the information necessary for the application of a multivariate analysis. We classified four types of phenazines into distinct clusters taking into account including planarity, ring-attached substituents, geometric arrangement and conjugation effects, energy maps as well as frontier orbitals energies. The experimental data and crystallochemical analysis obtained in the present study were able to substantiate the chemo-theoretical analysis. Our classifications agree well with experimental evidence regarding compounds that have already been studied. it would also be desirable to conduct new experimental studies in order to further evaluate the predicting capability of our calculations.

Apollon, a new Artemisia annua variety with high artemisinin content

Artemisinin, a sesquiterpene lactone endoperoxide isolated from the herb Artemisia annua L. (Asteraceae), is a highly potent antimalarial compound, which is efficient againt multidrug-resistant strains of Plasmodium falciparum. The promotion of artemisinin-based combination therapies (ACTs) by the WHO during the past years lead to a strong pressure on the world market of artemisinin. The artemisinin world market is volatile and therefore efforts to improve performance of this culture are often limited. The use of varieties with high artemisinin content is a key factor for the development of such cultures. This should secure the supply of artemisinin, lower its cost of production and improve the competitiveness of this new culture with other commercial crops. After the variety Artemis, Mediplant launches a new variety called Apollon with about 20% yield increase. Performances of this new hybrid, with artemisinin content nearing 1.6%, are being presented.

Southern Africa flora: a source of potential antimalarial compounds

Southern Africa flora: a source of potential antimalarial compounds

Exploring molecular docking and QSAR studies of plasmepsin-II inhibitor di-tertiary amines as potential antimalarial compounds

We report molecular docking and quantitative structure–activity relationship (QSAR) studies on plasmepsin-II inhibitor di-tertiary amines as antimalarial agents. The docking studies suggest that the molecules bind with a pocket of the enzyme formed by some non-polar amino acid residues (Ala219, Gly36, Gly216, Phe111, Phe120, Val78, Ileu32, Ileu123, Ileu290, Ileu300, Leu131 and Leu292) and some polar amino acid residues (Asp34, Asp214, Ser37, Ser218, Thr217, Tyr77 and Tyr192). Different QSAR models, obtained using various three-dimensional, physicochemical and/or topological descriptors and showing cross-validated predictive variance values (Q 2) ranging from 0.487 to 0.664 and the external predictive variance values () for the test set ranging from 0.534 to 0.579, support the statistical validity of the QSAR models.

Mechanism of growth inhibition of intraerythrocytic stages of Plasmodium falciparum by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)

Purine nucleotide synthesis in Plasmodium falciparum takes place solely by the purine salvage pathway in which preformed purine base(s) are salvaged from the host and acted upon by a battery of enzymes to generate AMP and GMP. Inhibitors of this pathway have a potent effect on the in vitro growth of P. falciparum and are hence, implicated as promising leads for the development of new generation anti-malarials. Here, we describe the mechanism of inhibition of the intraerythrocytic growth of P. falciparum by the purine nucleoside precursor, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Our results show that AICAR toxicity is mediated through the erythrocyte in which AICAR is phosphorylated to its nucleotide, ZMP. Further, purine metabolite labeling of the parasitized erythrocytes by [3H]-hypoxanthine, in the presence of AICAR, showed a significant decrease in radioactive counts in adenylate fractions but not in guanylate fractions. The most dramatic effect on parasite growth was observed when erythrocytes pretreated with AICAR were used in culture. Pretreatment of erythrocytes with AICAR led to significant intracellular accumulation of ZMP and these erythrocytes were incapable of supporting parasite growth. These results implicate that in addition to the purine salvage pathway in P. falciparum, AICAR alters the metabolic status of the erythrocytes, which inhibits parasite growth. As AICAR and ZMP are metabolites in the human serum and erythrocytes, our studies reported here throw light on their possible role in disease susceptibility, and also suggests the possibility of AICAR being a potential prophylactic or chemotherapeutic anti-malarial compound.