In Vitro Leishmanicidal Activity of Benzophenanthridine Alkaloids from Bocconia pearcei and Related Compounds

ABSTRACTConventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects againstLeishmania. In this study, thein vitroleishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested againstLeishmania majorandLeishmania amazonensisparasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated inL. amazonensisandL. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 thanL. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels ofLeishmaniagenes involved in the cell cycle, such astopoisomerase-2(TOP-2),PCNA, andMCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G1phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

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Leismanicidal Activity of Propolis Collected in the Semiarid Region of Brazil

Frontiers in Pharmacology ◽

10.3389/fphar.2021.702032 ◽

2021 ◽

Vol 12 ◽

Author(s):

Giani Maria Cavalcante ◽

Celso Amorim Camara ◽

Eva Monica Sarmento Da Silva ◽

Mariana Silva Santos ◽

Anderson Brandão Leite ◽

...

Keyword(s):

Cytotoxic Effect ◽

Ethanolic Extract ◽

Ultra Performance Liquid Chromatography ◽

Semiarid Region ◽

Array Detector ◽

Significant Activity ◽

Exact Mass ◽

Leishmanicidal Activity ◽

Etoh Extract

Objective: The aim of the current study is to investigate the chemical composition, cytotoxic effect, and leishmanicidal activity of propolis collected in the semi-arid region of Bahia, Brazil.Methods: EtOH extract, hexane, EtOAc and MeOH fractions from propolis were analyzed by ultra-performance liquid chromatography coupled with diode array detector and quadrupole time-of-flight mass spectrometry. The identification was based on the exact mass, general fragmentation behaviors and UV absorption of the flavonoids. The in vitro cytotoxic effect and leishmanicidal activity of ethanolic extract, hexane, ethyl acetate, and methanolic fractions of propolis were evaluated.Results: Five triterpenes and twenty-four flavonoids were identified. The propolis did not present toxicity to the host cell up to the maximum concentration tested. In addition, all tested samples showed statistically significant activity against promastigotes of Leishmania chagasi and Leishmania amazonensis. Regarding the activity against amastigote forms of L. amazonensis, the hexane fraction, presented statistically significant activity with IC50 of 1.3 ± 0.1 μg/ml.Conclusion: The results support the idea that propolis can be used for future antileishmania studies.

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Synthesis and Acivity of Chiral Amino Alcohols and Amides as New Cholinesterase Inhibitors for Alzheimer's Disease

10.21203/rs.3.rs-598122/v1 ◽

2021 ◽

Author(s):

Safak OZHAN KOCAKAYA ◽

Ismail Yener ◽

Abdulselam Ertaş ◽

Mehmet Karakaplan

Keyword(s):

Drug Candidate ◽

Molecular Dynamics Calculations ◽

The Right ◽

Potential Inhibitors ◽

Novel Drug ◽

Related Compounds ◽

Candidate Molecule ◽

Score Evaluation ◽

Novel Products

Abstract A series of biological active compounds 1–14 have been synthesized and used as potential inhibitors for AChE and BuChE. Potential inhibitor efficacy of these molecules to the target enzymes have been searched in vitro and theoretical by dock and molecular dynamic calculations. The results show that chiral amino alcohol compounds 6, 7 and 9 exhibited good value for medication scores. Among the tested compounds the best inhibition activities have been obtained with compounds 6 for AChE and BuChE by 87.68 and 92.46 % values, respectively at 50µg/mL concentration. The anticipated value of 6 also justified superb correlation with invitro statistics and it could be taken into consideration as drug candidate molecule for designing of novel drug. Potential inhibitory outcomes of those molecules on the right track proteins were investigated the use of Docking and Molecular Dynamics calculations. Dock score evaluation and Lipinski parameters have been proven those ligands are ability inhibitors against applicable enzymes. Our findings endorse that related compounds can be applied as a capacity supply of anti-alzheimer active molecules for designing novel products.

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Evidence that the metabolite repair enzyme NAD(P)HX epimerase has a moonlighting function

Bioscience Reports ◽

10.1042/bsr20180223 ◽

2018 ◽

Vol 38 (3) ◽

Cited By ~ 10

Author(s):

Thomas D. Niehaus ◽

Mona Elbadawi-Sidhu ◽

Lili Huang ◽

Laurence Prunetti ◽

Jesse F. Gregory ◽

...

Keyword(s):

Vitamin B6 ◽

Weakly Bound ◽

E Coli ◽

Essentially Normal ◽

Metabolite Repair ◽

Mutant Cells ◽

Dehydratase Activity ◽

Related Compounds

NAD(P)H-hydrate epimerase (EC 5.1.99.6) is known to help repair NAD(P)H hydrates (NAD(P)HX), which are damage products existing as R and S epimers. The S epimer is reconverted to NAD(P)H by a dehydratase; the epimerase facilitates epimer interconversion. Epimerase deficiency in humans causes a lethal disorder attributed to NADHX accumulation. However, bioinformatic evidence suggest caution about this attribution by predicting that the epimerase has a second function connected to vitamin B6 (pyridoxal 5′-phosphate and related compounds). Specifically, (i) the epimerase is fused to a B6 salvage enzyme in plants, (ii) epimerase genes cluster on the chromosome with B6-related genes in bacteria, and (iii) epimerase and B6-related genes are coexpressed in yeast and Arabidopsis. The predicted second function was explored in Escherichia coli, whose epimerase and dehydratase are fused and encoded by yjeF. The putative NAD(P)HX epimerase active site has a conserved lysine residue (K192 in E. coli YjeF). Changing this residue to alanine cut in vitro epimerase activity by ≥95% but did not affect dehydratase activity. Mutant cells carrying the K192A mutation had essentially normal NAD(P)HX dehydratase activity and NAD(P)HX levels, showing that the mutation had little impact on NAD(P)HX repair in vivo. However, these cells showed metabolome changes, particularly in amino acids, which exceeded those in cells lacking the entire yjeF gene. The K192A mutant cells also had reduced levels of ‘free’ (i.e. weakly bound or unbound) pyridoxal 5'-phosphate. These results provide circumstantial evidence that the epimerase has a metabolic function beyond NAD(P)HX repair and that this function involves vitamin B6.

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