Chloroquine-sensitive 3D7 Strain Of Plasmodium Falciparum Research Articles

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.

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.

Synthesis and Docking Study of 2–Aryl-4,5-diphenyl-1<i>H</i>-imidazole Derivatives as Lead Compounds for Antimalarial Agent

Series of 2-aryl-4,5-diphenyl-1H-imidazole derivatives of 2-(4-hydroxy-3-methoxyphenyl)-4,5-diphenyl-1H-imidazole (1), 2-(4,5-dimethoxyphenyl)-4,5-diphenyl-1H-imidazole (2) and 2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (3) were produced and evaluated for their in vitro antimalarial activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. A molecular docking study was also carried out against the crystal protein of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) (PDB ID: 1J3I.pdb) to predict the interaction between the compounds and protein. The physicochemical and pharmacokinetic parameters were computationally performed to predict the parameters of the absorption, distribution, metabolism, excretion, and toxicity (ADMET). Imidazoles were synthesized from aryl aldehyde derivatives with benzyl and ammonium acetate in glacial acetic acid using microwave-assisted-organic synthesis. Compounds 1, 2, and 3 were produced in 64.33, 50.56, and 70.55% yields, respectively. The IC50 of compounds 1, 2, and 3 against chloroquine-sensitive Plasmodium falciparum 3D7 strain was found to be 1.14, 5.28, and 2.42 µM, respectively. The molecular docking study agreed with the in vitro data by showing the lowest CDOCKER energy for compound 1 (-47.48 kcal/mol), followed by 3 (-43.79 kcal/mol) and 2 (-41.47 kcal/mol). The physicochemical and pharmacokinetic parameters showed that imidazoles 1, 2, and 3 obeyed Lipinski rules of five to propose as lead compounds for the antimalarial agents.

A Quantitative Structure-Activity Relationship Study on the Antimalarial Activities of 4-Aminoquinoline, Febrifugine and Artemisinin Compounds

Quantum chemical molecular descriptors representing different types of chemical reactivity were employed to investigate the antimalarial activities of 4-aminoquinoline, febrifugine, artemisinin and their derivatives. The quantitative structure-activity relationship results reveal that: (i) the antimalarial activities of 4-aminoquinoline compounds against the chloroquine-sensitive Plasmodium falciparum 3D7 strain are mainly affected by the electron flow and polarization interactions; (ii) The reactivity descriptors for the activities of febrifugine compounds against the chloroquine-resistant Plasmodium falciparum FCR-3 strain are the electron-acceptance chemical potential, the maximum nucleophilic and electrophilic local softness, the maximum positive charge of the hydrogen atom, etc.; (iii) The electron-donation chemical potential, the maximum negative charge, the inverse of the apolar surface area and the molar volume of artemisinin compounds are the most important descriptors for evaluating the activity against the chloroquine-resistant Plasmodium falciparum W-2 strain.

Chalcone analogue as potent anti-malarial compounds against Plasmodium falciparum: Synthesis, biological evaluation, and docking simulation study

ObjectiveTo investigate in vitro antimalarial activity of chalcone derivative compounds against Plasmodium falciparum 3D7 (Pf3D7) strain and in silico antimalarial activity. MethodsSynthesis of the chalcone derivatives was conducted via Claisen-Schmidt method using NaOH 60% base as catalyst. An in vitro antimalarial activity assay was carried out according to the Rieckmann method against the chloroquine-sensitive Pf3D7 strain. Molecular docking studies of the prepared compounds were performed using Discovery Studio 3.1 (Accelrys, Inc., San Diego, USA) software to dihydrofolate reductases–thymidylate synthase (PfDHFR-TS) protein with Protein Data Bank ID of 1J3I.pdb (sensitive-protein) and ID: 4DP3.pdb (resistance-protein). ResultsThis work has successfully synthesized seven chalcone derivatives with a great antimalarial activity. It has been revealed that allyloxy, hydroxy and alkoxy functional groups could increase the antimalarial activity of the chalcone derivatives. The best antimalarial activity of the prepared compounds was possessed by 3b with an IC50 value of 0.59 μM and categorized as an excellent antiplasmodial. Molecular docking studies of 3b showed binding interaction with the amino acid residues such as Ala16, Ile164, Phe58, Tyr170 of the 1J3I.pdb protein and also Ala16, Phe58, Ile112, Met55 of the 4DP3.pdb protein. ConclusionsAn in vitro antimalarial assay of the prepared chalcone derivative (3a–g) showed an excellent and good antiplasmodial activity against the chloroquine-sensitive Pf3D7 strain. In silico antimalarial studies revealed that 3a–g made binding interaction with both sensitive-protein (1J3I.pdb) and resistance-protein (4DP3.pdb), which means that they were both active against chloroquine-sensitive and resistant plasmodium strain.

Design, synthesis and antimalarial evaluation of novel thiazole derivatives

As part of our medicinal chemistry program’s ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.

Accelerated dereplication of crude extracts using HPLC–PDA–MS–SPE–NMR: Quinolinone alkaloids of Haplophyllum acutifolium

Direct hyphenation of analytical-scale high-performance liquid chromatography, photo-diode array detection, mass spectrometry, solid-phase extraction and nuclear magnetic resonance spectroscopy (HPLC–PDA–MS–SPE–NMR) has been used for accelerated dereplication of crude extract of Haplophyllum acutifolium (syn. Haplophyllum perforatum). This technique allowed fast on-line identification of six quinolinone alkaloids, named haplacutine A–F, as well as of acutine, haplamine, eudesmine, and 2-nonylquinolin-4(1 H)-one. Acutine and haplacutine E, isolated by preparative-scale HPLC, showed moderate antiplasmodial activity with IC 50 values of 2.17 ± 0.22 μM and 3.79 ± 0.24 μM, respectively (chloroquine-sensitive Plasmodium falciparum 3D7 strain).