Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

ABSTRACT A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 μM). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 μM, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

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New Amides Containing Selenium as Potent Leishmanicidal Agents Targeting Trypanothione Reductase

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00524-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e00524-20

Author(s):

Mikel Etxebeste-Mitxeltorena ◽

Daniel Plano ◽

Socorro Espuelas ◽

Esther Moreno ◽

Carlos Aydillo ◽

...

Keyword(s):

High Selectivity ◽

Selectivity Index ◽

Trypanothione Reductase ◽

Monocytic Cells ◽

Reference Drug ◽

Content Type ◽

Leishmanicidal Activity ◽

Drug Candidates ◽

Level Measurement ◽

Axenic Amastigotes

ABSTRACTTwo new series of 28 selenocyanate and diselenide derivatives containing amide moieties were designed, synthesized, and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC50 values lower than the reference drug miltefosine (EC50 = 2.84 μM). In addition, for six of them the selectivity index ranged from 9 to >1,442, greater than both references used. The most potent and selective compounds were compounds 2h, 2k, and 2m that displayed EC50 values of 0.52, 1.19, and 0.50 μM, respectively, and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1,442, >672, and >1,100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI values. They also showed interesting activity values against infected macrophages. Trypanothione reductase (TryR) activity and intracellular thiol level measurement assays were performed for the three best compounds in an attempt to elucidate their mechanism of action. Despite that the new analogs exhibited comparable or better inhibitory activities than the reference TryR inhibitors, more studies are necessary to confirm this result. In summary, our findings suggest that the three compounds described here could constitute leading leishmanicidal drug candidates.

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Leishmanicidal Activity of Isoselenocyanate Derivatives

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00904-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e00904-18 ◽

Cited By ~ 3

Author(s):

Celia Fernández-Rubio ◽

Esther Larrea ◽

José Peña Guerrero ◽

Eduardo Sesma Herrero ◽

Iñigo Gamboa ◽

...

Keyword(s):

Cell Cycle ◽

Amphotericin B ◽

Cell Cycle Progression ◽

Leishmania Major ◽

Antitumor Agents ◽

Peritoneal Macrophages ◽

Reference Drug ◽

Content Type ◽

Leishmanicidal Activity

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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Synthesis and Antibacterial Activity of Azetidinonyl Norfloxacin Congeners

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2015.8.3.11 ◽

2015 ◽

Vol 8 (3) ◽

pp. 2967-2971

Author(s):

Shalabh Sharma ◽

Kuldeep Kumar Saxena

Keyword(s):

Antibacterial Activity ◽

Schiff Bases ◽

Elemental Analysis ◽

Standard Drug ◽

Reference Drug ◽

E Coli ◽

Subtilis Atcc ◽

Structure Activity ◽

Drug Compound

Some novel Schiff bases and azetidinone congeners of norfloxacin have been synthesized and screened for antibacterial activity. The structures of compounds 1-ethyl-6-fluoro-7-piperazinyl-4-oxo-3-(substitutedarylidinylcarboxy- hydrazido)quinolines (2-6) and 1-ethyl-6-fluoro-7-pipera-zinyl-4-oxo-3-(3′-choloro-2′-oxo-4′-substitutedaryl-3′-aze-tidinyl)-aminocarboxy quinolines (7-11) were established by spectral and elemental analysis. The compounds 2-11 were evaluated in vitro against various strains of bacteria: E. coli ATCC 25922, B. subtilis ATCC 1633 and S. aureus ATCC 25923 to determine their antibacterial activity and feasible structure-activity relationships. The results of the study were compared with reference drug. Compound 8: 1-ethyl-6-fluoro-7-piperazinyl-4-oxo-3-(3′-choloro-2′-oxo-4′-(4′′-methoxyphenyl)-3′-azetidinyl)-aminocarboxyquinoline has displayed more potent antibacterial activity as compared to standard drug, chloramphenicol.

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In VitroActivities of Hexaazatrinaphthylenes against Leishmania spp.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00226-15 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2867-2874 ◽

Cited By ~ 13

Author(s):

Atteneri López-Arencibia ◽

Daniel García-Velázquez ◽

Carmen M. Martín-Navarro ◽

Ines Sifaoui ◽

María Reyes-Batlle ◽

...

Keyword(s):

Therapeutic Agents ◽

Content Type ◽

Inhibition Effect ◽

Intracellular Amastigotes ◽

Dependent Inhibition ◽

Leishmania Spp ◽

Dose Dependent Inhibition ◽

Dose Dependent ◽

Potential Use

ABSTRACTThein vitroactivity of a novel group of compounds, hexaazatrinaphthylene derivatives, against two species ofLeishmaniais described in this study. These compounds showed a significant dose-dependent inhibition effect on the proliferation of the parasites, with 50% inhibitory concentrations (IC50s) ranging from 1.23 to 25.05 μM against the promastigote stage and 0.5 to 0.7 μM against intracellular amastigotes. Also, a cytotoxicity assay was carried out to in order to evaluate the possible toxic effects of these compounds. Moreover, different assays were performed to determine the type of cell death induced after incubation with these compounds. The obtained results highlight the potential use of hexaazatrinaphthylene derivatives againstLeishmaniaspecies, and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.

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Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

Molecules ◽

10.3390/molecules24101901 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1901 ◽

Cited By ~ 1

Author(s):

Rui Min ◽

Weibin Wu ◽

Mingzhong Wang ◽

Lin Tang ◽

Dawei Chen ◽

...

Keyword(s):

Cellular Proliferation ◽

Parp Inhibitor ◽

Parp Inhibition ◽

Anticancer Activities ◽

Reference Drug ◽

Structure Activity ◽

Ic50 Values ◽

Proliferation Assays ◽

Parp 1

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by 1H-NMR, 13C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC50 values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well.

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Library of Seleno-Compounds as Novel Agents against Leishmania Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02546-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 13

Author(s):

Álvaro Martín-Montes ◽

Daniel Plano ◽

Rubén Martín-Escolano ◽

Verónica Alcolea ◽

Marta Díaz ◽

...

Keyword(s):

Parasite Species ◽

Low Cost ◽

Leishmania Species ◽

Leishmania Braziliensis ◽

Reference Drug ◽

Content Type ◽

Product Profile ◽

Low Toxicity ◽

Intracellular Amastigote

ABSTRACT The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.

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Synergistic Lethality of a Binary Inhibitor ofMycobacterium tuberculosisKasA

mBio ◽

10.1128/mbio.02101-17 ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 14

Author(s):

Pradeep Kumar ◽

Glenn C. Capodagli ◽

Divya Awasthi ◽

Riju Shrestha ◽

Karishma Maharaja ◽

...

Keyword(s):

Crystal Structure ◽

Cell Wall ◽

Mycobacterium Tuberculosis ◽

Substrate Binding ◽

Content Type ◽

X Ray ◽

Structure Activity Relationships ◽

Structure Activity ◽

Transcriptional Pattern

ABSTRACTWe report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) inMycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented thein vitroactivity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model ofM. tuberculosisinfection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCECell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors ofMycobacterium tuberculosisKasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

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Evaluation of Novel Chalcone-Thiosemicarbazones Derivatives as Potential Anti-Leishmania amazonensis Agents and Its HSA Binding Studies

Biomolecules ◽

10.3390/biom9110643 ◽

2019 ◽

Vol 9 (11) ◽

pp. 643

Author(s):

Mendes ◽

Goulart ◽

Chaves ◽

Faiões ◽

Canto-Carvalho ◽

...

Keyword(s):

Inhibitory Concentration ◽

Selectivity Index ◽

New Drugs ◽

Spectroscopic Techniques ◽

Binding Studies ◽

Reference Drug ◽

Intracellular Amastigotes ◽

Axenic Amastigotes ◽

Ic50 Values ◽

Pharmacokinetic Evaluation

A series of seven chalcone-thiosemicarbazones (5a–5g) were synthesized and evaluated as potential new drugs (anti-leishmanial effect). Although four of the chalcone-thiosemicarbazones are already known, none of them or any compound in this class has been previously investigated for their effects on parasites of the Leishmania genus. The compounds were prepared in satisfactory yields (40–75%) and these compounds were evaluated against promastigotes, axenic amastigotes and intracellular amastigotes of L. amazonensis after 48 h of culture. The half maximal inhibitory concentration (IC50) values of the intracellular amastigotes were determined to be in the range of 3.40 to 5.95 µM for all compounds assayed. The selectivity index showed value of 15.05 for 5a, whereas pentamidine (reference drug) was more toxic in our model (SI = 2.32). Furthermore, to understand the preliminary relationship between the anti-leishmanial activity of the chalcone-thiosemicarbazones, their electronic (σ), steric (MR) and lipophilicity (π) properties were correlated, and the results indicated that moieties with electronic withdrawing effects increase the anti-leishmanial activity. The preliminary pharmacokinetic evaluation of one of the most active compound (5e) was studied via interaction to human serum albumin (HSA) using multiple spectroscopic techniques combined with molecular docking. The results of antiparasitic effects against L. amazonensis revealed the chalcone-thiosemicarbazone class to be novel prototypes for drug development against leishmaniasis.

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Synthesis, Antitumor Activity, and Docking Analysis of New Pyrido[3’,2’:4,5]furo(thieno)[3,2-d]pyrimidin-8-amines

Molecules ◽

10.3390/molecules24213952 ◽

2019 ◽

Vol 24 (21) ◽

pp. 3952 ◽

Cited By ~ 3

Author(s):

Sirakanyan ◽

Spinelli ◽

Geronikaki ◽

Hakobyan ◽

Sahakyan ◽

...

Keyword(s):

Antitumor Activity ◽

Heterocyclic Compounds ◽

Phosphorus Oxychloride ◽

Docking Analysis ◽

Structure Activity ◽

Biological Tests ◽

Amino Derivatives ◽

Chloro Derivatives ◽

Derivatives Of

Continuing our research in the field of new heterocyclic compounds, herein we report on the synthesis and antitumor activity of new amino derivatives of pyrido[3’,2’:4,5](furo)thieno[3,2-d]pyrimidines as well as of two new heterocyclic systems: furo[2–e]imidazo[1,2-c]pyrimidine and furo[2,3-e]pyrimido[1,2-c]pyrimidine. Thus, by refluxing the 8-chloro derivatives of pyrido[3’,2’:4,5]thieno(furo)[3,2-d]pyrimidines with various amines, the relevant pyrido[3’,2’:4,5]thieno(furo)[3,2-d]pyrimidin-8-amines were obtained. Further, the cyclization of some amines under the action of phosphorus oxychloride led to the formation of new heterorings: imidazo[1,2-c]pyrimidine and pyrimido[1,2-c]pyrimidine. The possible antitumor activity of the newly synthesized compounds was evaluated in vitro. The biological tests evidenced that some of them showed pronounced antitumor activity. A study of the structure–activity relationships revealed that the compound activity depended mostly on the nature of the amine fragments. A docking analysis was also performed for the most active compounds.

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From in vitro to in cellulo: structure–activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa

Organic & Biomolecular Chemistry ◽

10.1039/c4ob00707g ◽

2014 ◽

Vol 12 (32) ◽

pp. 6094-6104 ◽

Cited By ~ 26

Author(s):

Michael P. Storz ◽

Giuseppe Allegretta ◽

Benjamin Kirsch ◽

Martin Empting ◽

Rolf W. Hartmann

Keyword(s):

Pseudomonas Aeruginosa ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity Relationships ◽

Structure Activity ◽

Relationship Of ◽

Derivatives Of

More than 60 derivatives of (2-nitrophenyl)methanol were synthesized and evaluated regarding their potency to inhibit PqsD. In vitro and in cellulo structure–activity relationships were derived.

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