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1.
Future Med Chem ; 16(2): 139-155, 2024 01.
Article in English | MEDLINE | ID: mdl-38131191

ABSTRACT

Aim: The assessment of the antileishmanial potential of 22 vanillin-containing 1,2,3-triazole derivatives against Leishmania braziliensis is reported. Materials & methods: Initial screening was performed against the parasite promastigote form. The most active compound, 4b, targeted parasites within amastigotes (IC50 = 4.2 ± 1.0 µmol l-1), presenting low cytotoxicity and a selective index value of 39. 4D quantitative structure-activity relationship and molecular docking studies provided insights into structure-activity and biological effects. Conclusion: A vanillin derivative with significant antileishmanial activity was identified. Enhanced activity was linked to increased electrostatic and Van der Waals interactions near the benzyl ring of the derivatives. Molecular docking indicated the inhibition of the Leishmania amazonensis sterol 14α-demethylase, using Leishmania infantum sterol 14α-demethylase as a model, without affecting the human isoform. Inhibition was active site competition with lanosterol.


Subject(s)
Antiprotozoal Agents , Benzaldehydes , Quantitative Structure-Activity Relationship , Humans , Molecular Docking Simulation , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Triazoles/pharmacology , Sterols , Structure-Activity Relationship
2.
Exp Parasitol ; 238: 108269, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35526574

ABSTRACT

Leishmaniasis is a group of neglected vector-borne tropical diseases caused by protozoan parasites of the genus Leishmania that multiply within phagocytic cells and have a wide range of clinical manifestations. Cutaneous leishmaniasis (CL) is a serious public health that affects more than 98 countries, putting 350 million people at risk. There are no vaccines that have been proven to prevent CL, and the treatment relies on drugs that often have severe side effects, justifying the search for new antileishmanial treatments. In the present investigation, it is demonstrated that 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1H-1,2,3-triazole (7k) presents significant antileishmanial activity (IC50 of 7.4 µmol L-1 and 1.6 µmol L-1 for promastigote and amastigote forms, respectively), low cytotoxicity against macrophage cells (IC50 of 211.9 µmol L-1), and a selective index of 132.5. Under similar conditions, compound 7k outperformed glucantime and pentamidine, two commonly used drugs in clinics. In vivo assays on CL-infected female BALB/c mice demonstrated that compound 7k had activity similar to intralesional glucantime when administered orally, with decreased lesion and parasitic load, and a low systemic toxic effect. Given the importance of understanding the relationship between compound structure and biological activity in the research and development of new drugs, the development of a quantitative structure-activity relationship (QSAR) model for the leishmanicidal activity presented by the eugenol derivatives with 1,2,3-triazole functionalities is also described herein. This study demonstrates the therapeutic potential of orally active eugenol derivatives against CL and provides useful insights into the relationship between the chemical structures of triazolic eugenol derivatives and their biological profile.


Subject(s)
Antiprotozoal Agents , Leishmaniasis, Cutaneous , Leishmaniasis , Animals , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/toxicity , Eugenol/pharmacology , Eugenol/therapeutic use , Female , Humans , Leishmaniasis/drug therapy , Leishmaniasis, Cutaneous/drug therapy , Meglumine Antimoniate/therapeutic use , Mice , Quantitative Structure-Activity Relationship , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/therapeutic use
3.
Rev Soc Bras Med Trop ; 53: e20200091, 2020.
Article in English | MEDLINE | ID: mdl-32578713

ABSTRACT

INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations. METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.


Subject(s)
Antiprotozoal Agents/therapeutic use , Leishmania mexicana/drug effects , Leishmaniasis, Cutaneous/drug therapy , Quinolines/therapeutic use , Animals , Disease Models, Animal , Female , Leishmaniasis, Cutaneous/parasitology , Mice , Mice, Inbred BALB C , Parasite Load , Quinolines/chemistry
4.
Rev. Soc. Bras. Med. Trop ; 53: e20200091, 2020. graf
Article in English | Sec. Est. Saúde SP, Coleciona SUS, LILACS | ID: biblio-1136875

ABSTRACT

Abstract INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations. METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.


Subject(s)
Animals , Female , Quinolines/therapeutic use , Leishmania mexicana/drug effects , Leishmaniasis, Cutaneous/drug therapy , Antiprotozoal Agents/therapeutic use , Quinolines/chemistry , Leishmaniasis, Cutaneous/parasitology , Disease Models, Animal , Parasite Load , Mice , Mice, Inbred BALB C
5.
Exp Parasitol ; 195: 78-86, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30385267

ABSTRACT

Currently, available treatment options for leishmaniasis are limited and unsatisfactory. In a previous study, a quinoline derivative (AMQ-j), exhibited a strong effect against Leishmania amazonensis and its antileishmanial activity was preliminarily associated with mitochondrial dysfunction. The present study further explores the antileishmanial effect of this compound against L. amazonensis, as well as determines the main cellular processes involved in the death of the parasite. Moreover, this study evaluated the in vivo effect of the AMQ-j in BALB/c mice experimentally infected by L. amazonensis. The results showed that the compound AMQ-j induces a set of morphological and biochemical features that could correlate with both autophagy-related and apoptosis-like processes, indicating intense mitochondrial swelling, a collapse of the mitochondrial membrane potential, an abnormal chromatin condensation, an externalization of phosphatidylserine, an accumulation of lipid bodies, a disorganization of cell cycle, a formation of autophagic vacuoles, and an increase of acidic compartments. Treatment with AMQ-j through an intralesional route was effective in reducing the parasite burden and size of the lesion. No significant increase in the serum levels of hepatic or renal damage toxicity markers was observed. These findings contribute to the understanding of the mode of action of quinoline derivatives involved in the death of Leishmania parasites and encourage new studies in other experimental models of Leishmania infection.


Subject(s)
Aminoquinolines/pharmacology , Antiprotozoal Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Leishmania mexicana/drug effects , Leishmaniasis, Cutaneous/drug therapy , Aminoquinolines/therapeutic use , Aminoquinolines/toxicity , Animals , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/toxicity , Cell Cycle/drug effects , Chlorocebus aethiops , Creatinine/metabolism , Ear, External/parasitology , Ear, External/pathology , Female , Inhibitory Concentration 50 , Kidney/drug effects , Leishmania mexicana/cytology , Leishmania mexicana/growth & development , Leishmania mexicana/ultrastructure , Liver/drug effects , Liver/enzymology , Mice , Mice, Inbred BALB C , Vero Cells
6.
Eur J Med Chem ; 146: 274-286, 2018 Feb 25.
Article in English | MEDLINE | ID: mdl-29407957

ABSTRACT

In this paper, it is described the synthesis and the evaluation of the leishmanicidal activity of twenty-six eugenol derivatives bearing 1,2,3-triazole functionalities. The evaluation of the compounds on promastigotes of Leishmania amazonensis (WHOM/BR/75/Josefa) showed that eugenol derivatives present leishmanicidal activities with varying degrees of effectiveness. The most active compound, namely 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1H-1,2,3-triazole (7k) (IC50 = 7.4 ±â€¯0.8 µmol L-1), also targeted Leishmania parasites inside peritoneal macrophages (IC50 = 1.6 µmol L-1) without interfering with cell viability. The cytotoxicity of 7k against macrophage cells presented IC50 of 211.9 µmol L-1 and the selective index was equal to 132.5. Under similar conditions, compound 7k was more effective than glucantime and pentamidine, two drugs currently in the clinic. In addition, theoretical calculations showed that this compound also presents most physicochemical and pharmacokinetic properties within the ranges expected for orally available drugs. It is believed that eugenol bearing 1,2,3-triazole functionalities may represent a scaffold to be explored toward the development of new agents to treat leishmaniasis.


Subject(s)
Antiprotozoal Agents/pharmacology , Eugenol/pharmacology , Leishmania/drug effects , Macrophages/drug effects , Triazoles/pharmacology , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Eugenol/chemical synthesis , Eugenol/chemistry , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Triazoles/chemistry
7.
Vaccine ; 25(12): 2168-72, 2007 Mar 08.
Article in English | MEDLINE | ID: mdl-17240003

ABSTRACT

We previously showed that intranasal (i.n.) vaccination with pCIneo plasmid encoding the leishmanial LACK gene (pCIneo-LACK) induces long-lasting protective immunity against cutaneous leishmaniasis in mice. In this work, we proposed to investigate whether the efficacy of i.n. pCIneo-LACK is extensive to visceral leishmaniasis. BALB/c mice received two i.n. doses of 30 microg pCIneo-LACK prior to intravenous (i.v.) infection with Leishmania chagasi. Vaccinated mice developed significantly lower parasite burden in the liver and spleen than control mice receiving empty pCIneo or saline. The spleen cells of vaccinated mice produced significantly increased IFN-gamma and IL-4 concomitant with decreased IL-10 production during infection. Serum levels of specific IgG were elevated whereas TNF-alpha were decreased as compared with controls. These results show that the practical needle-free i.n. pCIneo-LACK vaccine displays potential broad-spectrum activity against leishmaniasis.


Subject(s)
Antigens, Protozoan/immunology , Leishmaniasis, Cutaneous/immunology , Leishmaniasis, Visceral/immunology , Protozoan Proteins/immunology , Protozoan Vaccines/immunology , Administration, Intranasal , Animals , Antigens, Protozoan/genetics , DNA, Protozoan/genetics , Interferon-gamma/metabolism , Interleukin-4/metabolism , Leishmaniasis, Cutaneous/parasitology , Leishmaniasis, Cutaneous/prevention & control , Leishmaniasis, Visceral/genetics , Liver/drug effects , Liver/parasitology , Mice , Mice, Inbred BALB C , Plasmids/administration & dosage , Protozoan Proteins/genetics , Protozoan Vaccines/administration & dosage , Protozoan Vaccines/genetics , Spleen/drug effects , Spleen/metabolism , Spleen/parasitology , Treatment Outcome
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