Copper-Catalyzed Asymmetric Hydroboration Reaction of Novel Methylene Isoindolinone Compounds through Microwave Irradiation and Their Antileishmanial and Antitoxoplasma Activities.

The aim of this study was devoted into molecular docking calculations to discover the potential antileishmania and antitoxoplasma activities of newly synthesized compounds obtained by applying a practical and simple method under microwave irradiation. All these compounds were tested in vitro for their biological activity against Leishmania major promastigotes, amastigotes, and Toxoplasma gondii tachyzoites. Compounds 2a, 5a, and 5e were the most active against both L. major promastigotes and amastigotes, with IC50 values of less than 0.4 µM mL-1. Compounds 2c, 2e, 2h, and 5d had a strong antitoxoplasma activity of less than 2.1 µM mL-1 against T. gondii. We can conclude that aromatic methyleneisoindolinones are potently active against both L. major and T. gondii. Further studies for mode of action evaluation are recommended. Compounds 5c and 5b are the best drug candidates for antileishmania and antitoxoplasma due to their SI values being over 13. The docking studies of compounds 2a-h and 5a-e against pteridine reductase 1 and T. gondii enoyl acyl carrier protein reductase reveal that compound 5e may be an effective antileishmanial and antitoxoplasma drug discovery initiative.

Versatile anti-infective properties of pyrido- and dihydropyrido[2,3-d]pyrimidine-based compounds.

A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic and viral RNase H inhibitory activity. Several compounds showed considerable activity against Toxoplasma gondii parasites and Leishmania major amastigotes, which warrants further investigation. Based on the structural similarities of certain derivatives with common viral RNase H inhibitors, a HIV-1 RNase H assay was used to study the RNase H inhibition by selected test compounds. Docking of active derivatives into the active site of the HIV-1 RNase H enzyme was carried out. The new compound 2a, inactive in the antiparasitic tests, showed distinct HIV-1 RNase H inhibition. Thus, ring substitution determines antiparasitic or HIV-1 RNase H inhibitory activity of this promising compound class.

Regiospecific Reduction of 4,6-Dinitrobenzimidazoles: Synthesis, Characterization, and Biological Evaluation.

The regiospecific reduction of 4,6-dinitrobenzimidazole derivatives leading to the corresponding 4-amino-6-nitrobenzimidazoles was studied. The identification of the formed product structures was accomplished by spectroscopic and X-ray diffraction data. The anticancer and antiparasitic activities of the synthesized compounds were examined, and promising activities against Toxoplasma gondii and Leishmania major parasites were discovered for certain 4,6-dinitrobenzimidazoles in addition to moderate anticancer activities of the 4-amino-6-nitrobenzimidazole derivatives against T. gondii cells. However, the tumor cell experiments revealed a promising sensitivity of p53-negative colon cancer cells to these compounds.

Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 µM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 µM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

Evaluation of Ruthenium(II) N-Heterocyclic Carbene Complexes as Enzymatic Inhibitory Agents with Antioxidant, Antimicrobial, Antiparasitical and Antiproliferative Activity.

A series of [RuCl2(p-cymene)(NHC)] complexes were obtained by reacting [RuCl2(p-cymene)]2 with in situ generated Ag-N-heterocyclic carbene (NHC) complexes. The structure of the obtained complexes was determined by the appropriate spectroscopy and elemental analysis. In addition, we evaluated the biological activities of these compounds as antienzymatic, antioxidant, antibacterial, anticancer, and antiparasitic agents. The results revealed that complexes 3b and 3d were the most potent inhibitors against AchE with IC50 values of 2.52 and 5.06 µM mL-1. Additionally, 3d proved very good antimicrobial activity against all examined microorganisms with IZ (inhibition zone) over 25 mm and MIC (minimum inhibitory concentration) < 4 µM. Additionally, the ligand 2a and its corresponding ruthenium (II) complex 3a had good cytotoxic activity against both cancer cells HCT-116 and HepG-2, with IC50 values of (7.76 and 11.76) and (4.12 and 9.21) µM mL-1, respectively. Evaluation of the antiparasitic activity of these complexes against Leishmania major promastigotes and Toxoplasma gondii showed that ruthenium complexes were more potent than the free ligand, with an IC50 values less than 1.5 µM mL-1. However, 3d was found the best one with SI (selectivity index) values greater than 5 so it seems to be the best candidate for antileishmanial drug discovery program, and much future research are recommended for mode of action and in vivo evaluation. In general, Ru-NHC complexes are the most effective against L. major promastigotes.

An Update on Natural Antileishmanial Treatment Options from Plants, Fungi and Algae.

Efficient drugs for the treatment of leishmaniasis, which is classified as a neglected tropical disease, are sought for. This review covers potential drug candidates from natural plant, fungus and algae sources, which were described over the last six years. The identification of these natural antileishmanials often based on the knowledge of traditional medicines. Crucial insights into the activities of these natural remedies against Leishmania parasites and against infections caused by these parasites in laboratory animals or patients are provided and compared with selected former active examples published more than six years ago. In addition, immuno-modulatory natural antileishmanials and recent developments on combination therapies including natural products and approved antileishmanials are discussed. The described natural products revealed promising data warranting further efforts on the discovery and development of new antileishmanials based on patterns from nature.

Activity of Fluorinated Curcuminoids against Leishmania major and Toxoplasma gondii Parasites.

A new 3,4-difluorobenzylidene analog of curcumin, CDF, was recently reported, which demonstrated significantly enhanced bioavailability and in vivo anticancer activity compared with curcumin. For highlighting the antiparasitic behavior of CDF, we tested this compound together with its new O-methylated analog MeCDF against Leishmania major and Toxoplasma gondii parasites. Both CDF and MeCDF were tested in vitro against L. major and T. gondii. In addition, the in vitro cytotoxicity against Vero cells and macrophages was determined and selectivity indices were calculated. The DPPH radical scavenging activity assay was carried out in order to determine the antioxidant activity of the test compounds. Both compounds showed high activities against both parasite forms with EC50 values in the (sub-)micromolar range (0.35 to 0.8 µM for CDF, 0.31 to 1.2 µM for MeCDF). The higher activity of CDF against L. major amastigotes when compared with MeCDF can in parts be attributed to the antioxidant activity of CDF while MeCDF lacking any antioxidant activity was more active than CDF against T. gondii parasites. In conclusion, CDF and MeCDF are promising antiparasitic drug candidates due to their high activities against L. major and T. gondii parasites.

p-Trifluoromethyl- and p-pentafluorothio-substituted curcuminoids of the 2,6-di[(E)-benzylidene)]cycloalkanone type: Syntheses and activities against Leishmania major and Toxoplasma gondii parasites.

A series of the title curcuminoids with structural variance in the heteroatom of the cycloalkanone and the p-substituents of the phenyl rings were tested for their activities against Leishmania major and Toxoplasma gondii parasites. The majority of them showed high activities against both parasite forms with EC50 values in the sub-micromolar concentration range. Bis(p-pentafluorothio)-substituted 3,5-di[(E)-benzylidene]piperidin-4-one 1b was not just noticeable antiparasitic, but also exhibited a considerable selectivity for L. major promastigotes over normal Vero cells. While derivatives differing only in the p-phenyl substituents being CF3 or SF5 showed similar antiparasitic activities, the cyclic ketone hub was more decisive both for the anti-parasitic activities and the selectivities for the parasites vs. normal cells. QSAR calculations confirmed the observed structure-activity relations and suggested structural variations for a further improvement of the antiparasitic activity. Docking studies based on DFT calculations revealed L. major pteridine reductase 1 as a likely molecular target protein of the title compounds.

New Pyrano-4H-benzo[g]chromene-5,10-diones with Antiparasitic and Antioxidant Activities.

New pyranonaphthoquinone derivatives were synthesized and investigated for their activity against Trypanosoma brucei, Leishmania major, and Toxoplasma gondii parasites. The pentafluorophenyl derivative was efficacious against T. brucei with single digit micromolar EC50 values and against T. gondii with even sub-micromolar values. The 3-chloro-4,5-dimethoxyphenyl derivative showed an activity against amastigotes of Leishmania major parasites comparable to that of amphotericin B. In addition, antioxidant activities were observed for the bromophenyl derivatives, and their redox behavior was studied by cyclovoltammetry. Anti-parasitic and antioxidative activities of the new naphthoquinone derivatives appear uncorrelated.

Evaluation of the antiparasitic activities of imidazol-2-ylidene-gold(I) complexes.

A series of cationic gold(I)-carbene complexes with various 4,5-diarylimidazolylidene ligands were either newly prepared or repurposed for testing against protozoal Leishmania major, Toxoplasma gondii, and Trypanosoma brucei parasites. The syntheses of the new complexes 1b and 1c were described. Ferrocene compound 1a showed the highest activities against L. major amastigotes and T. gondii and distinct selectivity for T. gondii cells when compared with the activity against nonmalignant Vero cells. The ferrocene derivatives 1a-c are generally more active against the L. major amastigotes and the T. gondii tachyzoites than the other tested anisyl gold complexes and the approved drugs atovaquone and amphotericin B. Compounds 1a and 1e showed the highest selectivities for L. major amastigotes. Compounds 1d and 1f showed the highest selectivities for L. major promastigotes; 1f was the most active compound against L. major promastigotes of this series of compounds. The 3,4,5-trimethoxyphenyl analog 1b also exhibited a much greater selectivity for T. b. brucei cells when compared with its activity against human HeLa cells.

New Antiparasitic Bis-Naphthoquinone Derivatives.

A series of bis-naphthoquinone derivatives prepared by condensation of aryl aldehydes with lawsone were tested for antiparasitic activities against Toxoplasma gondii and Trypanosoma brucei parasites. Monofluorophenyl derivative 1a, 3,4-difluorophenyl analog 1c and furyl compound 1l exhibited significant activity against T. gondii cells and appear to be new promising drug candidates against this parasite. The 3,4,5-trifluorophenyl derivative 1g and the isovanillyl derivative 1j displayed selective activity against Leishmania major amastigotes.