Design, synthesis and anti-leishmanial activity of novel symmetrical bispyridinium cyclophanes

Gómez-Pérez, Verónica; Manzano, José Ignacio; García-Hernández, Raquel; Castanys, Santiago; Gamarro, Francisco; Campos, Joaquı́n M.

doi:10.1016/j.ejmech.2014.10.040

Cited by 11 publications

(12 citation statements)

References 25 publications

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“…The sensitivity for VGP-318 is similar in both promastigotes and intracellular amastigotes overexpressing CEK and EK versus control parasites (Table 6). This result suggests that the anti-leishmanial activity of these compounds is not related to the CEK and EK enzymes [15].…”

Section: Drug Susceptibility Assay Of L Donovani Lines Overexpressinmentioning

confidence: 85%

“…We have synthesized a new family of symmetrical bis-pyridinium diazacyclophanes designed as cyclic analogues of previously reported acyclic bis-pyridinium derivatives, by cyclization through the exocyclic nitrogen atoms at position 4 of the pyridinium moiety via linker 2, which leads to the diazacyclophane targets ( Figure 3) [15]. These compounds have been evaluated against L. major and L. donavani.…”

Section: Symmetrical Bis-pyridinium Diazacyclophanesmentioning

confidence: 99%

“…The final nine cyclophanes were tested as anti-leishmanial agents against promastigotes and intracellular amastigotes of L. donovani and L. major [15]. The results are shown in Table 5, where miltefosine and AmB were used as reference drugs.…”

Section: Anti-leishmanial Activitymentioning

confidence: 99%

“…Compound VGP-318 was chosen as a representative compound to further investigate the mechanism of action of this new family of compounds [15]. This compound shows promising activity against intracellular amastigotes of L. major (EC 50 1.3 ± 0.3 μM), with a selectivity index (122) higher than those of AmB (51) and miltefosine (30).…”

Section: Anti-leishmanial Activitymentioning

confidence: 99%

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Symmetrical Pyridinium-Phanes and –Diazacyclophanes — Promising Heterocyclic Scaffolds for the Development of Anti-Leishmanial Agents

Campos¹,

Gómez-Pérez²,

Castanys³

et al. 2016

Scope of Selective Heterocycles From Organic and Pharmaceutical Perspective

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There is an urgent need for better drugs for a more successful fight against leishmaniasis, one of the most important neglected diseases caused by the parasite Leishmania. We have recently synthesized several symmetrical pyridinium compounds belonging to two different series: bis-pyridinium and bis-quinolinium acyclic structures and bis-pyridinium diazacyclophanes derivatives. The first series of bis-pyridinium derivatives have been found to display activity against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major, with EC 50 values lower than 1 μM. The majority of compounds show a similar behavior in both Leishmania species, being slightly more active against intracellular amastigotes of L. major. The series of bis-pyridinium diazacyclophanes can be considered as rigid analogues of the previous bis-cationic ones. The activity of these compounds has also been evaluated against promastigotes and intracellular amastigotes of L. donovani and L. major. All the diazacyclophanes are more active against L. major, with EC 50 values of between 1 and 17 μM in intracellular amastigotes, and in some cases they present a higher selectivity index than the reference anti-leishmanial drugs such as amphotericin B and miltefosine. In conclusion, these bis-quaternary compounds represent promising candidates as potential therapeutic agents against leishmaniasis.

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Section: Drug Susceptibility Assay Of L Donovani Lines Overexpressinmentioning

confidence: 85%

Section: Symmetrical Bis-pyridinium Diazacyclophanesmentioning

confidence: 99%

Section: Anti-leishmanial Activitymentioning

confidence: 99%

Section: Anti-leishmanial Activitymentioning

confidence: 99%

See 2 more Smart Citations

Symmetrical Pyridinium-Phanes and –Diazacyclophanes — Promising Heterocyclic Scaffolds for the Development of Anti-Leishmanial Agents

Campos¹,

Gómez-Pérez²,

Castanys³

et al. 2016

Scope of Selective Heterocycles From Organic and Pharmaceutical Perspective

Self Cite

View full text Add to dashboard Cite

show abstract

“…The synthesis of several molecules showing leishmanicidal activity and that of new lead compounds, such as β‐carboline alkaloids, [ 10 ] piperonylaminoacid conjugates, [ 11 ] heteroretinoid‐bis(benzylidene)ketones, [ 12 ] and bispyridinium cyclophanes, have also been described. [ 13 ] In addition, the drawbacks associated with the currently available treatments have led to the development of new strategies aiming at leishmaniasis control. In this context, special attention has been given to nitroaromatic scaffolds, as such compounds are used to treat a wide variety of diseases, including Parkinson's disease, angina, and insomnia, [ 14–16 ] as well as several infections caused either by bacteria or by a range of pathogenic protozoan parasites as reported over the past 60 years.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and leishmanicidal evaluation of sulfanyl‐ and sulfonyl‐tethered functionalized benzoate derivatives featuring a nitroimidazole moiety

Rodríguez

Gutiérrez

Domínguez

et al. 2020

Archiv der Pharmazie

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A series of new nitroimidazole-containing derivatives was synthesized by coupling of 2-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio]ethanol with diversely substituted benzoic acids. Upon treatment with m-CPBA, 12 of these sulfanyl compounds were further oxidized to their sulfonyl analogs. All the 26 synthetic compounds were examined for in vitro activity against Leishmania (V.) braziliensis and Leishmania (L.) mexicana, and some of them displayed an efficient antileishmanial activity. Among the compounds tested, the catecholic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4-dihydroxybenzoate (9a, LC 50 = 13 and 11 µM) and the pyrogallolic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4,5-trihydroxybenzoate (9b, LC 50 = 4 and 1 µM) were the most active ones against the two Leishmania strains. K E Y W O R D S antiproliferative agents, nitroimidazole, synthesis 1 | INTRODUCTION Leishmaniasis is an infectious disease caused by protozoa of the genus Leishmania. A recent review has shown that over 98 countries and territories are endemic for leishmaniasis transmission, with an overall prevalence of 12 million cases. Over 20 Leishmania species known to be infective to humans are transmitted by the bite of infected female phlebotomine sandflies, thus causing three main types of leishmaniasis: visceral (VL), cutaneous (CL), and mucocutaneous (MCL). It is estimated that approximately 0.2-0.4 million of new VL cases and 0.7-1.2 million of new CL cases occur each year. These diseases are responsible annually for approximately S C H E M E 1 Synthesis of the 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}ethyl benzoate derivatives 7a-l and 9a,b 2 of 10 | RODRÍGUEZ ET AL.

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In vitro evaluation and in vivo efficacy of nitroimidazole-sulfanyl ethyl derivatives against Leishmania (V.) braziliensis and Leishmania (L.) mexicana

et al. 2021

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The aim of this study was to synthesize several small molecules of the type 5-nitroimidazole-sulfanyl and evaluate biological properties against the main Leishmania species that cause cutaneous leishmaniasis in Venezuela. Final compounds 4-7 were generated through simple nucleophilic substitution of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole 3 with 2-mercaptoethanol, 1-methyl-2-mercaptoethanol, and 2-thyolacetic acid derivative. Compound 8 was synthesized via a coupling reaction between 7 and (S)-Methyl 2-amino-4-methylpentanoate hydrochloride. The inhibitory concentrations of (3, 4, 7, 8) against Leishmania (L.) mexicana and (V.) braziliensis in promastigotes and experimentally infected macrophages were determined by in vitro activity assays. Compounds 7 and 8 shown high activity against both species of Leishmania and were selected for the in vivo evaluation. Animals were infected with promastigotes of the two species and divided into four groups of ten ( 10) animals and a control group. Intralesional injection way was used for the treatment. The parasitological diagnostic after treatment was obtained by PCR using species specific oligonucleotides. The two Leishmania species were susceptible to compounds 7 and 8 in vivo assays. The results indicated that both compounds reduce significantly (96%) the size of the lesion and cure 63% of the mice infected with L (L) mexicana or L (V) braziliensis as was determined by PCR. The results are indicating that both compounds may represent an alternative treatment for these two Leishmania species.

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Design, synthesis and anti-leishmanial activity of novel symmetrical bispyridinium cyclophanes

Cited by 11 publications

References 25 publications

Symmetrical Pyridinium-Phanes and –Diazacyclophanes — Promising Heterocyclic Scaffolds for the Development of Anti-Leishmanial Agents

Symmetrical Pyridinium-Phanes and –Diazacyclophanes — Promising Heterocyclic Scaffolds for the Development of Anti-Leishmanial Agents

Synthesis and leishmanicidal evaluation of sulfanyl‐ and sulfonyl‐tethered functionalized benzoate derivatives featuring a nitroimidazole moiety

In vitro evaluation and in vivo efficacy of nitroimidazole-sulfanyl ethyl derivatives against Leishmania (V.) braziliensis and Leishmania (L.) mexicana

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