Chemical Constituents of Macaranga occidentalis, Antimicrobial and Chemophenetic Studies.

Medicinal plants are known as sources of potential antimicrobial compounds belonging to different classes. The aim of the present work was to evaluate the antimicrobial potential of the crude extract, fractions, and some isolated secondary metabolites from the leaves of Macaranga occidentalis, a Cameroonian medicinal plant traditionally used for the treatment of microbial infections. Repeated column chromatography of the ethyl acetate and n-butanol fractions led to the isolation of seventeen previously known compounds (1-17), among which three steroids (1-3), one triterpene (4), four flavonoids (5-8), two stilbenoids (9 and 10) four ellagic acid derivatives (11-14), one geraniinic acid derivative (15), one coumarine (16), and one glyceride (17). Their structures were elucidated mainly by means of extensive spectroscopic and spectrometric (1D and 2D NMR and, MS) analysis and comparison with the published data. The crude extract, fractions, and isolated compounds were all screened for their antimicrobial activity. None of the natural compounds was active against Candida strains. However, the crude extract, fractions, and compounds showed varying levels of antibacterial properties against at least one of the tested bacterial strains, with minimal inhibitory concentrations (MICs) ranging from 250 to 1000 µg/mL. The n-butanol (n-BuOH) fraction was the most active against Escherichia coli ATCC 25922, with an MIC value of 250 µg/mL. Among the isolated compounds, schweinfurthin B (10) exhibited the best activity against Staphylococcus aureus NR 46003 with a MIC value of 62.5 µg/mL. In addition, schweinfurthin O (9) and isomacarangin (6) also exhibited moderate activity against the same strain with a MIC value of 125 µg/mL. Therefore, pharmacomodulation was performed on compound 6 and three new semisynthetic derivatives (6a-c) were prepared by allylation and acetylation reactions and screened for their in vitro antimicrobial activity. None of the semisynthetic derivatives showed antimicrobial activity against the same tested strains. The chemophenetic significance of the isolated compounds is also discussed in this paper.

Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

7-Chloroquinolinehydrazones as First-in-Class Anticancer Experimental Drugs in the NCI-60 Screen among Different Investigated Series of Aryl, Quinoline, Pyridine, Benzothiazole and Imidazolehydrazones.

In the context of a continuously increasing global cancer risk, the search for new effective and affordable anticancer drugs remains a constant demand. This study describes chemical experimental drugs able to destroy cancer cells by arresting their growth. New hydrazones with quinoline, pyridine, benzothiazole and imidazole moieties have been synthesized and evaluated for their cytotoxic potential against 60 cancer cell lines. 7-Chloroquinolinehydrazones were the most active in the current study and exhibited good cytotoxic activity with submicromolar GI50 values on a large panel of cell lines from nine tumor types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer). This study provided consistent structure-activity relationships in this series of experimental antitumor compounds.

CDATA[Recent Advances in the Development of 1,2,3-Triazole-containing Derivatives as Potential Antifungal Agents and Inhibitors of Lanoster ol 14α-Demethylase.

1,2,3-Triazole, a five-membered heterocyclic nucleus, is widely recognized as a key chromophore of great value in medicinal chemistry for delivering compounds possessing innumerable biological activities, including antimicrobial, antitubercular, antidiabetic, antiviral, antitumor, antioxidants, and anti-inflammatory activities. Mainly, in the past years, diverse conjugates carrying this biologically valuable core have been reported due to their attractive fungicidal potential and potent effects on various infective targets. Hence, hybridization of 1,2,3-triazole with other antimicrobial pharmacophores appears to be a judicious strategy to develop new effective anti-fungal candidates to combat the emergence of drug-sensitive and drug-resistant infectious diseases. Thus, the current review highlights the recent advances of this promising category of 1,2,3-triazole-containing hybrids incorporating diverse varieties of bioactive heterocycles such as conozole, coumarin, imidazole, benzimidazole, pyrazole, indole, oxindole, chromene, pyrane, quinazoline, chalcone, isoflavone, carbohydrates, and amides. It underlies their inhibition behavior against a wide array of infectious fungal species during 2015-2020.

Original antileishmanial hits: Variations around amidoximes.

In continuation to our previous findings on amidoximes' antiparasitic activities, a new series of 23 original derivatives was designed and obtained by convergent synthesis. First, new terminal alkenes were synthesized by cross-coupling reaction. Then, cyclization was performed between terminal alkenes and ß-ketosulfones using manganese(III) acetate reactivity. Twenty-three amidoximes were tested for their in vitro activity against Leishmania amazonensis promastigotes and their toxicity on murine macrophages. Seven of the tested compounds exhibited an antileishmanial activity at lower than 10 µM with moderate to low toxicity. Six of these molecules showed activity at lower than 10 µM against promastigotes and toxicity at higher than 50 µM were selected and evaluated for their activity against intracellular Leishmania amazonensis amastigotes. Modulating chemical substituents in position 2 of dihydrofuran highly influenced their antileishmanial activities. The introduction of a methyl or trifluoromethyl group on the benzene ring of the benzyl group had a positive influence on activity without significantly increasing toxicity (52, 59, 60).

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions.

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 µm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 µm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study.

Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 µM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).

Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium.

A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains. They were neither cytotoxic (CC50 15-50 µM) toward HepG2 and CHO cells, nor mutagenic. Structure-activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages.

New series of monoamidoxime derivatives displaying versatile antiparasitic activity.

Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R(1), R(2) or R(3) substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 µM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 µM). Modulating chemical substituents in R(2) and R(3) only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.