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1.
Pak J Pharm Sci ; 37(1(Special)): 173-184, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38747267

ABSTRACT

Hydrazones 1-6, azo-pyrazoles 7-9 and azo-pyrimidines 10-15 are compounds that exhibit antibacterial activity. The mode of action and structures of these derivatives have been previously confirmed as antibacterial. In this investigation, biological screening and molecular docking studies were performed for derivatives 1-15, with compounds 2, 7, 8, 14 and 15 yielding the best energy scores (from -20.7986 to -10.5302 kcal/mol). Drug-likeness and in silico ADME prediction for the most potent derivatives, 2, 7, 8, 14 and 15, were predicted (from 84.46 to 96.85%). The latter compounds showed good recorded physicochemical properties and pharmacokinetics. Compound 8 demonstrated the strongest inhibition, which was similar to the positive control (eflornithine) against Trypanosoma brucei brucei (WT), with an EC50 of 25.12 and 22.52µM, respectively. Moreover, compound 14 exhibited the best activity against Leishmania mexicana promastigotes and Leishmania major promastigotes (EC50 =46.85; 40.78µM, respectively).


Subject(s)
Molecular Docking Simulation , Pyrazoles , Pyrimidines , Trypanocidal Agents , Trypanosoma brucei brucei , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Trypanosoma brucei brucei/drug effects , Pyrazoles/pharmacology , Pyrazoles/chemistry , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/chemical synthesis , Leishmania mexicana/drug effects , Leishmania major/drug effects , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Computer Simulation , Azo Compounds/pharmacology , Azo Compounds/chemistry , Azo Compounds/chemical synthesis , Structure-Activity Relationship , Parasitic Sensitivity Tests
2.
Chem Biol Drug Des ; 103(5): e14535, 2024 May.
Article in English | MEDLINE | ID: mdl-38772877

ABSTRACT

Despite efforts, available alternatives for the treatment of leishmaniasis are still scarce. In this work we tested a class of 15 quinolinylhydrazone analogues and presented data that support the use of the most active compound in cutaneous leishmaniasis caused by Leishmania amazonensis. In general, the compounds showed activity at low concentrations for both parasitic forms (5.33-37.04 µM to promastigotes, and 14.31-61.98 µM to amastigotes). In addition, the best compound (MHZ15) is highly selective for the parasite. Biochemical studies indicate that the treatment of promastigotes with MHZ15 leads the loss of mitochondrial potential and increase in ROS levels as the primary effects, which triggers accumulation of lipid droplets, loss of plasma membrane integrity and apoptosis hallmarks, including DNA fragmentation and phosphatidylserine exposure. These effects were similar in the intracellular form of the parasite. However, in this parasitic form there is no change in plasma membrane integrity in the observed treatment time, which can be attributed to metabolic differences and the resilience of the amastigote. Also, ultrastructural changes such as vacuolization suggesting autophagy were observed. The in vivo effectiveness of MHZ15 in the experimental model of cutaneous leishmaniasis was carried out in mice of the BALB/c strain infected with L. amazonensis. The treatment by intralesional route showed that MHZ15 acted with great efficiency with significantly reduction in the parasite load in the injured paws and draining lymph nodes, without clinical signs of distress or compromise of animal welfare. In vivo toxicity was also evaluated and null alterations in the levels of hepatic enzymes aspartate aminotransferase, and alanine aminotransferase was observed. The data presented herein demonstrates that MHZ15 exhibits a range of favorable characteristics conducive to the development of an antileishmanial agent.


Subject(s)
Apoptosis , Hydrazones , Leishmaniasis, Cutaneous , Mice, Inbred BALB C , Mitochondria , Animals , Apoptosis/drug effects , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Hydrazones/pharmacology , Hydrazones/chemistry , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/parasitology , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/therapeutic use , Leishmania/drug effects , Reactive Oxygen Species/metabolism , Female , Leishmania mexicana/drug effects , Membrane Potential, Mitochondrial/drug effects
3.
J Med Chem ; 67(10): 8323-8345, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38722757

ABSTRACT

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.


Subject(s)
Antiprotozoal Agents , Leishmania donovani , Leishmania mexicana , Animals , Structure-Activity Relationship , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacokinetics , Mice , Leishmania donovani/drug effects , Leishmania mexicana/drug effects , Drug Discovery , Humans , Female , Leishmaniasis/drug therapy , Mice, Inbred BALB C
4.
PLoS Negl Trop Dis ; 18(5): e0012175, 2024 May.
Article in English | MEDLINE | ID: mdl-38768213

ABSTRACT

In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is prevalent for these clinical forms of the disease and also has high rates of HIV infection. Here, we characterized the drug susceptibility of a L. amazonensis clinical isolate from a 46-year-old man with diffuse cutaneous leishmaniasis coinfected with HIV from this endemic area. This patient underwent several therapeutic regimens with meglumine antimoniate, liposomal amphotericin B, and pentamidine, without success. In vitro susceptibility assays against promastigotes and intracellular amastigotes demonstrated that this isolate had low susceptibility to amphotericin B, when compared with the reference strain of this species that is considered susceptible to antileishmanial drugs. Additionally, we investigated whether the low in vitro susceptibility would affect the in vivo response to amphotericin B treatment. The drug was effective in reducing the lesion size and parasite burden in mice infected with the reference strain, whereas those infected with the clinical isolate and a resistant line (generated experimentally by stepwise selection) were refractory to amphotericin B treatment. To evaluate whether the isolate was intrinsically resistant to amphotericin B in animals, infected mice were treated with other drugs that had not been used in the treatment of the patient (miltefosine, paromomycin, and a combination of both). Our findings demonstrated that all drug schemes were able to reduce lesion size and parasite burden in animals infected with the clinical isolate, confirming the amphotericin B-resistance phenotype. These findings indicate that the treatment failure observed in the patient may be associated with amphotericin B resistance, and demonstrate the potential emergence of amphotericin B-resistant L. amazonensis isolates in an area of Brazil endemic for cutaneous leishmaniasis.


Subject(s)
Amphotericin B , Antiprotozoal Agents , Drug Resistance , Amphotericin B/pharmacology , Amphotericin B/therapeutic use , Animals , Brazil , Middle Aged , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Humans , Male , Mice , Leishmania/drug effects , Leishmania/isolation & purification , Leishmania/classification , Leishmania mexicana/drug effects , Leishmania mexicana/isolation & purification , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/parasitology , HIV Infections/complications , HIV Infections/drug therapy , Parasitic Sensitivity Tests , Mice, Inbred BALB C , Leishmaniasis, Diffuse Cutaneous/parasitology , Leishmaniasis, Diffuse Cutaneous/drug therapy
5.
Acta Trop ; 254: 107189, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38522630

ABSTRACT

Cutaneous leishmaniasis (CL) is a vector-borne disease characterized by skin lesions that can evolve into high-magnitude ulcerated lesions. Thus, this study aimed to develop an innovative nanoemulsion (NE) with clove oil, Poloxamer® 407, and multiple drugs, such as amphotericin B (AmB) and paromomycin (PM), for use in the topical treatment of CL. METHODS: Droplet size, morphology, drug content, stability, in vitro release profile, in vitro cytotoxicity on RAW 264.7 macrophages, and antileishmanial activity using axenic amastigotes of Leishmania amazonensis were assessed for NEs. RESULTS: After optimizing the formulation parameters, such as the concentration of clove oil and drugs, using an experimental design, it was possible to obtain a NE with an average droplet size of 40 nm and a polydispersion index of 0.3, and these parameters were maintained throughout the 365 days. Furthermore, the NE showed stability of AmB and PM content for 180 days under refrigeration (4 °C), presented a pH compatible with the skin, and released modified AmB and PM. NE showed the same toxicity as free AmB and higher toxicity than free PM against RAW 264.7 macrophages. The same activity as free AmB, and higher activity than free PM against amastigotes L. amazonensis. CONCLUSION: It is possible to develop a NE for the treatment of CL; however, complementary studies regarding the antileishmanial activity of NE should be carried out.


Subject(s)
Amphotericin B , Antiprotozoal Agents , Emulsions , Leishmaniasis, Cutaneous , Paromomycin , Paromomycin/pharmacology , Paromomycin/administration & dosage , Amphotericin B/pharmacology , Amphotericin B/administration & dosage , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/parasitology , Animals , Mice , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/chemistry , RAW 264.7 Cells , Macrophages/drug effects , Macrophages/parasitology , Leishmania mexicana/drug effects , Clove Oil/pharmacology , Clove Oil/chemistry , Poloxamer/chemistry , Drug Stability , Nanoparticles/chemistry
6.
Exp Parasitol ; 260: 108743, 2024 May.
Article in English | MEDLINE | ID: mdl-38513973

ABSTRACT

Treatment against leishmaniasis presents problems, mainly due to the toxicity of the drugs, high cost, and the emergence of resistant strains. A previous study showed that two vanillin-derived synthetic molecules, 3s [4-(2-hydroxy-3-(4-octyl-1H-1,2,3-triazol-1-yl)propoxy)-3-methoxybenzaldehyde] and 3t [4-(3-(4-decyl-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)-3-methoxybenzaldehyde], presented antileishmanial activity against Leishmania infantum, L. amazonensis, and L. braziliensis species. In the present work, 3s and 3t were evaluated to treat L. amazonensis-infected mice. Molecules were used pure or incorporated into Poloxamer 407-based micelles. In addition, amphotericin B (AmpB) and its liposomal formulation, Ambisome®, were used as control. Animals received the treatment and, one and 30 days after, they were euthanized to evaluate immunological, parasitological, and biochemical parameters. Results showed that the micellar compositions (3s/Mic and 3t/Mic) induced significant reductions in the lesion mean diameter and parasite load in the infected tissue and distinct organs, as well as a specific and significant antileishmanial Th1-type immune response, which was based on significantly higher levels of IFN-γ, IL-12, nitrite, and IgG2a isotype antibodies. Drug controls showed also antileishmanial action; although 3s/Mic and 3t/Mic have presented better and more significant parasitological and immunological data, which were based on significantly higher IFN-γ production and lower parasite burden in treated animals. In addition, significantly lower levels of urea, creatinine, alanine transaminase, and aspartate transaminase were found in mice treated with 3s/Mic and 3t/Mic, when compared to the others. In conclusion, results suggest that 3s/Mic and 3t/Mic could be considered as therapeutic candidates to treat against L. amazonensis infection.


Subject(s)
Antiprotozoal Agents , Benzaldehydes , Leishmania mexicana , Mice, Inbred BALB C , Micelles , Animals , Mice , Benzaldehydes/pharmacology , Benzaldehydes/chemistry , Leishmania mexicana/drug effects , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/chemistry , Leishmaniasis, Cutaneous/drug therapy , Female , Amphotericin B/pharmacology , Amphotericin B/therapeutic use , Poloxamer/chemistry , Poloxamer/pharmacology , Male , Spleen/parasitology
7.
Parasitology ; 151(5): 506-513, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38533610

ABSTRACT

Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-ß-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.


Subject(s)
Disease Models, Animal , Leishmania mexicana , Leishmaniasis, Cutaneous , Mice, Inbred BALB C , Animals , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/parasitology , Mice , Female , Male , Leishmania mexicana/drug effects , Tubercidin/pharmacology , Tubercidin/analogs & derivatives , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/administration & dosage , Macrophages, Peritoneal/parasitology , Macrophages, Peritoneal/drug effects , Leishmania/drug effects
8.
Parasitol Int ; 86: 102458, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34509671

ABSTRACT

Leishmaniasis chemotherapy is a bottleneck in disease treatment. Although available, chemotherapy is limited, toxic, painful, and does not lead to parasite clearance, with parasite resistance also being reported. Therefore, new therapeutic options are being investigated, such as plant-derived anti-parasitic compounds. Amentoflavone is the most common biflavonoid in the Selaginella genus, and its antileishmanial activity has already been described on Leishmania amazonensis intracellular amastigotes but its direct action on the parasite is controversial. In this work we demonstrate that amentoflavone is active on L. amazonensis promastigotes (IC50 = 28.5 ± 2.0 µM) and amastigotes. Transmission electron microscopy of amentoflavone-treated promastigotes showed myelin-like figures, autophagosomes as well as enlarged mitochondria. Treated parasites also presented multiple lipid droplets and altered basal body organization. Similarly, intracellular amastigotes presented swollen mitochondria, membrane fragments in the lumen of the flagellar pocket as well as autophagic vacuoles. Flow cytometric analysis after TMRE staining showed that amentoflavone strongly decreased mitochondrial membrane potential. In silico analysis shows that amentoflavone physic-chemical, drug-likeness and bioavailability characteristics suggest it might be suitable for oral administration. We concluded that amentoflavone presents a direct effect on L. amazonensis parasites, causing mitochondrial dysfunction and parasite killing. Therefore, all results point for the potential of amentoflavone as a promising candidate for conducting advanced studies for the development of drugs against leishmaniasis.


Subject(s)
Biflavonoids/pharmacology , Leishmania mexicana/physiology , Mitochondria/physiology , Selaginellaceae/chemistry , Biflavonoids/chemistry , Leishmania mexicana/drug effects , Mitochondria/drug effects , Trypanocidal Agents
9.
Int J Mol Sci ; 22(24)2021 Dec 19.
Article in English | MEDLINE | ID: mdl-34948408

ABSTRACT

Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 µM and 82 µM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.


Subject(s)
Antiprotozoal Agents/pharmacology , Arginase/antagonists & inhibitors , Benzimidazoles/pharmacology , Leishmania mexicana/drug effects , Protozoan Proteins/antagonists & inhibitors , Animals , Antiprotozoal Agents/chemistry , Arginase/metabolism , Benzimidazoles/chemistry , Cell Line , Drug Discovery , Humans , Leishmania mexicana/enzymology , Leishmania mexicana/physiology , Leishmaniasis, Cutaneous/drug therapy , Mice , Models, Molecular , Protozoan Proteins/metabolism
10.
ChemistryOpen ; 10(9): 896-903, 2021 09.
Article in English | MEDLINE | ID: mdl-34499412

ABSTRACT

Research for innovative drugs is crucial to contribute to parasitic infections control and eradication. Inspired by natural antiprotozoal triterpenes, a library of 12 hemisynthetic 3-O-arylalkyl esters was derived from ursolic and oleanolic acids through one-step synthesis. Compounds were tested on Trypanosoma, Leishmania and the WI38 cell line alongside with a set of triterpenic acids. Results showed that the triterpenic C3 esterification keeps the antitrypanosomal activity (IC50 ≈1.6-5.5 µm) while reducing the cytotoxicity compared to parent acids. Unsaturation of the ester alkyl chain leads to an activity loss interestingly kept when a sterically hindered group replaces the double bond or shields the ester group. An ursane/oleanane C3 hydroxylation was the only important feature for antileishmanial activity. Two candidates, dihydrocinnamoyl and 2-fluorophenylpropionyl ursolic acids, were tested on an acute mouse model of African trypanosomiasis with significant parasitemia reduction at day 5 post-infection for the dihydrocinnamoyl derivative. Further evaluation on other alkyl/protective groups should be investigated both in vitro and in vivo.


Subject(s)
Esters/pharmacology , Triterpenes/pharmacology , Trypanocidal Agents/pharmacology , Animals , Drug Design , Drug Evaluation, Preclinical , Esters/chemical synthesis , Esters/toxicity , Female , Leishmania mexicana/drug effects , Mice , Parasitic Sensitivity Tests , Triterpenes/chemical synthesis , Triterpenes/toxicity , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/toxicity , Trypanosoma brucei brucei/drug effects
11.
Int Immunopharmacol ; 100: 108130, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34500286

ABSTRACT

Leishmaniasis is a set of infectious diseases with high rates of morbidity and mortality, it affects millions of people around the world. Treatment, mainly with pentavalent antimonials, presents significant toxicity and many cases of resistance. In previous works we have demonstrated the effective and selective antileishmanial activity of Eugenia uniflora L. essential oil, being constituted (47.3%) by the sesquiterpene curzerene. Considering the high rate of parasite inhibition demonstrated for E. uniflora essential oil, and the significant presence of curzerene in the oil, this study aimed to evaluate its antileishmania activity and possible mechanisms of action. Curzerene was effective in inhibiting the growth of promastigotes (IC50 3.09 ± 0.14 µM) and axenic amastigotes (EC50 2.56 ± 0.12 µM), with low cytotoxicity to RAW 264.7 macrophages (CC50 83.87 ± 4.63 µM). It was observed that curzerene has direct effects on the parasite, inducing cell death by apoptosis with secondary necrotic effects (producing pores in the plasma membrane). Curzerene proved to be even more effective against intra-macrophage amastigote forms, with an EC50 of 0.46 ± 0.02 µM. The selectivity index demonstrated by curzerene on these parasite forms was 182.32, being respectively 44.15 and 8.47 times more selective than meglumine antimoniate and amphotericin B. The antiamastigote activity of curzerene was associated with immunomodulatory activity, as it increased TNF-α, IL-12, and NO levels, and lysosomal activity, and decreased IL-10 and IL-6 cytokine levels detected in macrophages infected and treated. In conclusion, our results demonstrate that curzerene is an effective and selective antileishmanial agent, a candidate for in vivo investigation in models of antileishmanial activity.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania mexicana/drug effects , Sesquiterpenes/pharmacology , Animals , Antiprotozoal Agents/therapeutic use , Apoptosis/drug effects , Humans , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-12/metabolism , Interleukin-6/metabolism , Leishmania mexicana/growth & development , Macrophages/drug effects , Mice , Mice, Transgenic , Molecular Docking Simulation , RAW 264.7 Cells , Tumor Necrosis Factor-alpha/metabolism
12.
Exp Parasitol ; 229: 108154, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34481863

ABSTRACT

The compound 3-bromopyruvate (3-BrPA) is well-known and studies from several researchers have demonstrated its involvement in tumorigenesis. It is an analogue of pyruvic acid that inhibits ATP synthesis by inhibiting enzymes from the glycolytic pathway and oxidative phosphorylation. In this work, we investigated the effect of 3-BrPA on energy metabolism of L. amazonensis. In order to verify the effect of 3-BrPA on L. amazonensis glycolysis, we measured the activity level of three glycolytic enzymes located at different points of the pathway: (i) glucose kinases, step 1, (ii) glyceraldehyde 3-phosphate dehydrogenase (GAPDH), step 6, and (iii) enolase, step 9. 3-BrPA, in a dose-dependent manner, significantly reduced the activity levels of all the enzymes. In addition, 3-BrPA treatment led to a reduction in the levels of phosphofruto-1-kinase (PFK) protein, suggesting that the mode of action of 3-BrPA involves the downregulation of some glycolytic enzymes. Measurement of ATP levels in promastigotes of L. amazonensis showed a significant reduction in ATP generation. The O2 consumption was also significantly inhibited in promastigotes, confirming the energy depletion effect of 3-BrPA. When 3-BrPA was added to the cells at the beginning of growth cycle, it significantly inhibited L. amazonensis proliferation in a dose-dependent manner. Furthermore, the ability to infect macrophages was reduced by approximately 50% when promastigotes were treated with 3-BrPA. Taken together, these studies corroborate with previous reports which suggest 3-BrPA as a potential drug against pathogenic microorganisms that are reliant on glucose catabolism for ATP supply.


Subject(s)
Leishmania mexicana/drug effects , Leishmaniasis, Diffuse Cutaneous/parasitology , Pyruvates/pharmacology , Animals , Blotting, Western , Brazil , Cricetinae , Humans , Leishmania mexicana/enzymology , Leishmania mexicana/growth & development , Leishmania mexicana/metabolism , Macrophages/parasitology , Mice , Oxygen Consumption/drug effects , Phosphopyruvate Hydratase/metabolism , RAW 264.7 Cells
13.
ChemMedChem ; 16(22): 3396-3401, 2021 11 19.
Article in English | MEDLINE | ID: mdl-34357687

ABSTRACT

A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis.


Subject(s)
Amidines/pharmacology , Antiparasitic Agents/pharmacology , Drug Development , Leishmania mexicana/drug effects , Pentamidine/pharmacology , Amidines/chemistry , Antiparasitic Agents/chemical synthesis , Antiparasitic Agents/chemistry , Dose-Response Relationship, Drug , Drug Resistance/drug effects , Molecular Structure , Parasitic Sensitivity Tests , Pentamidine/chemical synthesis , Pentamidine/chemistry , Structure-Activity Relationship
14.
Parasitol Res ; 120(9): 3307-3317, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34370070

ABSTRACT

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.


Subject(s)
Antiprotozoal Agents , Leishmania braziliensis , Leishmania mexicana , Leishmaniasis, Cutaneous , Nitroimidazoles , Animals , Antiprotozoal Agents/pharmacology , Leishmania braziliensis/drug effects , Leishmania mexicana/drug effects , Leishmaniasis, Cutaneous/drug therapy , Mice , Nitroimidazoles/pharmacology
15.
Molecules ; 26(13)2021 Jun 26.
Article in English | MEDLINE | ID: mdl-34206940

ABSTRACT

Ethanolic extracts of samples of temperate zone propolis, four from the UK and one from Poland, were tested against three Trypanosoma brucei strains and displayed EC50 values < 20 µg/mL. The extracts were fractionated, from which 12 compounds and one two-component mixture were isolated, and characterized by NMR and high-resolution mass spectrometry, as 3-acetoxypinobanksin, tectochrysin, kaempferol, pinocembrin, 4'-methoxykaempferol, galangin, chrysin, apigenin, pinostrobin, cinnamic acid, coumaric acid, cinnamyl ester/coumaric acid benzyl ester (mixture), 4',7-dimethoxykaempferol, and naringenin 4',7-dimethyl ether. The isolated compounds were tested against drug-sensitive and drug-resistant strains of T. brucei and Leishmania mexicana, with the highest activities ≤ 15 µM. The most active compounds against T. brucei were naringenin 4',7 dimethyl ether and 4'methoxy kaempferol with activity of 15-20 µM against the three T. brucei strains. The most active compounds against L. mexicana were 4',7-dimethoxykaempferol and the coumaric acid ester mixture, with EC50 values of 12.9 ± 3.7 µM and 13.1 ± 1.0 µM. No loss of activity was found with the diamidine- and arsenical-resistant or phenanthridine-resistant T. brucei strains, or the miltefosine-resistant L. mexicana strain; no clear structure activity relationship was observed for the isolated compounds. Temperate propolis yields multiple compounds with anti-kinetoplastid activity.


Subject(s)
Leishmania mexicana/drug effects , Propolis/analysis , Propolis/pharmacology , Trypanocidal Agents/chemistry , Trypanosoma brucei brucei/drug effects , Cinnamates/chemistry , Flavanones/chemistry , Flavonoids/chemistry , Kaempferols/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Poland , Propolis/chemistry , United Kingdom
16.
Arch Pharm (Weinheim) ; 354(10): e2100081, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34323311

ABSTRACT

The indan-1,3-dione and its derivatives are important building blocks in organic synthesis and present important biological activities. Herein, the leishmanicidal and cytotoxicity evaluation of 16 2-arylidene indan-1,3-diones is described. The compounds were evaluated against the leukemia cell lines HL60 and Nalm6, and the most effective ones were 2-(4-nitrobenzylidene)-1H-indene-1,3(2H)-dione (4) and 4-[(1,3-dioxo-1H-inden-2(3H)-ylidene)methyl]benzonitrile (10), presenting IC50 values of around 30 µmol/L against Nalm6. The leishmanicidal activity was assessed on Leishmania amazonensis, with derivative 4 (IC50 = 16.6 µmol/L) being the most active. A four-dimensional quantitative structure-activity analysis (4D-QSAR) was applied to the indandione derivatives, through partial least-squares regression. The statistics presented by the regression models built with the selected field descriptors of Coulomb (C) and Lennard-Jones (L) nature, considering the activities against L. amazonensis, HL60, and Nalm6 leukemia cells, were, respectively, R2 = 0.88, 0.92, and 0.98; Q2 = 0.83, 0.88, and 0.97. The presence of positive Coulomb descriptors near the carbonyl groups indicates that these polar groups are related to the activities. Besides, the presence of positive Lennard-Jones descriptors close to substituents R3 or R1 indicates that bulky nonpolar substituents in these positions tend to increase the activities. This study provides useful insights into the mode of action of indandione derivatives for each biological activity involved.


Subject(s)
Antineoplastic Agents/pharmacology , Antiprotozoal Agents/pharmacology , Indans/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cell Line, Tumor , HL-60 Cells , Humans , Indans/chemical synthesis , Indans/chemistry , Inhibitory Concentration 50 , Leishmania mexicana/drug effects , Leukemia/drug therapy , Quantitative Structure-Activity Relationship
17.
Biomed Pharmacother ; 141: 111910, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34323692

ABSTRACT

Leishmaniasis is a group of neglected tropical diseases whose treatment with antimonials bears limitations and has changed little in over 80 years. Medicinal plants have been evaluated as a therapeutic alternative for leishmaniasis. Arrabidaea chica is popularly used as a wound healing and antiparasitic agent, especially as leishmanicidal agent. This study examined the leishmanicidal activity of a crude extract (ACCE), an anthocyanidin-rich fraction (ACAF), and three isolated anthocyanidins from A. chica: carajurin, 3'-hydroxy-carajurone, and carajurone. We evaluated the antileishmanial activity against promastigote and intracellular amastigote forms of Leishmania amazonensis and determined cytotoxicity in BALB/c peritoneal macrophages, as well as nitrite quantification, using the Griess method. Molecular docking was carried out to evaluate interactions of carajurin at the nitric oxide synthase enzyme. All compounds were active against promastigotes after 72 h, with IC50 values of 101.5 ± 0.06 µg/mL for ACCE and 4.976 ± 1.09 µg/mL for ACAF. Anthocyanidins carajurin, 3'-hydroxy-carajurone, and carajurone had IC50 values of 3.66 ± 1.16, 22.70 ± 1.20, and 28.28 ± 0.07 µg/mL, respectively. The cytotoxicity assay after 72 h showed results ranging from 9.640 to 66.74 µg/mL for anthocyanidins. ACAF and carajurin showed selectivity against intracellular amastigote forms (SI> 10), with low cytotoxicity within 24 h, a statistically significant reduction in all infection parameters, and induced nitrite production. Molecular docking studies were developed to understand a possible mechanism of activation of the nitric oxide synthase enzyme, which leads to an increase in the production of nitric oxide observed in the other experiments reported. These results encourage us to suggest carajurin as a biological marker of A. chica.


Subject(s)
Anthocyanins/pharmacology , Antiprotozoal Agents/pharmacology , Leishmania mexicana/drug effects , Animals , Leishmaniasis, Cutaneous/drug therapy , Macrophages, Peritoneal/drug effects , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Nitric Oxide Synthase/antagonists & inhibitors , Plant Extracts/pharmacology , Plant Leaves/chemistry , Plants, Medicinal
18.
Biomed Pharmacother ; 141: 111857, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34323702

ABSTRACT

Quinoline and 1,2,3-triazoles are well-known nitrogen-based heterocycles presenting diverse pharmacological properties, although their antileishmanial activity is still poorly exploited. As an effort to contribute with studies involving these interesting chemical groups, in the present study, a series of compounds derived from 4-aminoquinoline and 1,2,3-triazole were synthetized and biological studies using L. amazonensis species were performed. The results pointed that the derivative 4, a hybrid of 4-aminoquinoline/1,2,3-triazole exhibited the best antileishmanial action, with inhibitory concentration (IC50) values of ~1 µM against intramacrophage amastigotes of L. amazonensis , and being 16-fold more active to parasites than to the host cell. The mechanism of action of derivative 4 suggest a multi-target action on Leishmania parasites, since the treatment of L. amazonensis promastigotes caused mitochondrial membrane depolarization, accumulation of ROS products, plasma membrane permeabilization, increase in neutral lipids, exposure of phosphatidylserine to the cell surface, changes in the cell cycle and DNA fragmentation. The results suggest that the antileishmanial effect of this compound is primarily altering critical biochemical processes for the correct functioning of organelles and macromolecules of parasites, with consequent cell death by processes related to apoptosis-like and necrosis. No up-regulation of reactive oxygen and nitrogen intermediates was promoted by derivative 4 on L. amazonensis -infected macrophages, suggesting a mechanism of action independent from the activation of the host cell. In conclusion, data suggest that derivative 4 presents selective antileishmanial effect, which is associated with multi-target action, and can be considered for future studies for the treatment against disease.


Subject(s)
Aminoquinolines/pharmacology , Antiprotozoal Agents/pharmacology , Leishmania mexicana/drug effects , Triazoles/pharmacology , Aminoquinolines/chemical synthesis , Animals , Antiprotozoal Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Membrane/chemistry , Cell Membrane/metabolism , DNA Fragmentation/drug effects , Female , Lipid Metabolism/drug effects , Macrophages/parasitology , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred BALB C , Organelles/drug effects , Phosphatidylserines/pharmacology , Reactive Oxygen Species/metabolism , Triazoles/chemical synthesis
19.
Parasitol Int ; 84: 102376, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33951539

ABSTRACT

Leishmaniasis is one of the most relevant neglected tropical diseases in the world, affecting 14 million people. Despite the high morbidity, mortality and socio-economic impact, few therapeutic options are available for this disease. To make matters worse, the available molecules have several limitations such as limited efficacy, high cost, side effects and increased resistance. In this context, our group previously synthesized new compounds with anti-leishmania potential being the bis(N-[4-(hydroxyphenyl)methyl]-2-pyridinemethamine)zinc perchlorate monohydrate 4 (complex 4) the most promising one. Therefore, this present work revealed some morphological and physiological changes promoted by complex 4 on Leishmania amazonensis promastigotes as well as it was evidenced its potential against intramacrophage amastigotes. Complex 4 promoted a progressive reduction on the promastigotes size and a remarkable increase on the granularity/complexity as judged by flow cytometry. Transmission electron microscopy (TEM) analysis revealed extensive mitochondrial and plasma membrane alterations, although plasma membrane integrity remained. The mitochondrial changes observed by TEM were accompanied by a decrease in the activity of mitochondrial dehydrogenases with increased production of reactive oxygen species. Interestingly, promastigotes also showed changes in lipid metabolism. Besides the very low toxicity to macrophages, complex 4 had a great effect on intramacrophage amastigotes, displaying an IC50 of 3.91 µM. Collectively, the data presented here reinforce the potential of aminopyridyl compounds complexed to zinc against L. amazonensis. Thus, our work serves as a basis for in vivo assays to be designed or even the synthesis of more selective/effective compounds with lower cost.


Subject(s)
Leishmania mexicana/drug effects , Trypanocidal Agents/pharmacology , Leishmaniasis/drug therapy , Perchlorates/pharmacology
20.
Parasitol Int ; 83: 102342, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33831578

ABSTRACT

Leishmaniasis is a neglected broad clinical spectrum disease caused by protozoa of the genus Leishmania, which affect millions of people annually in the world and the treatment has severe side effects and resistant strains have been reported. Mesoionic salts are a subclass of the betaine group with extensive biological activity such as microbicide and anti-inflammatory In this work, we analyze the cytotoxic effects of mesoionic salts, 4-phenyl-5-(X-phenyl)-1,3,4-thiadiazolium-2-phenylamine chloride (X = 4 Cl; 3,4 diCl and 3,4 diF), on Leishmania amazonensis in vitro. Initially, Mesoionic salts toxicity were evaluated by XTT assay on L. amazonensis promastigotes. Our results show that the mesoionic salts MI-3,4 diCl, MI-4 Cl and MI-3,4 diF were toxic to the promastigote parasite with IC50 values of 14.3, 40.1 and 61.8 µM, respectively. The amastigote survival was evaluated in treated infected-macrophages, and the results demonstrate that MI-4 Cl (IC50 = 33 µM) and MI-3,4 diCl (IC50 = 43 µM) have a toxic effect against these forms. None of the mesoionic compounds tested present host cell toxicity up to the tested concentration of 100 µM. The selectivity index for MI-3,4 diCl and MI-4 Cl were 3.94 and 6.97, respectively. Nitric oxide (NO) production assayed by Griess reagent, in LPS-activated macrophages or not, in the presence of the salts showed that only the MI-3,4 diCl compound reduced NO levels. Lipid profile analysis of treated-promastigotes showed no alteration of neutral lipids. Evaluation of mitochondrial membrane potential (∆Ψm) showed that the MI-4Cl compound was able to reduce (∆Ψm) by 50%. Therefore, our results suggest that the chlorinated compounds are promising biomolecules, which cause inhibition of L.amazonensis promastigotes, amastigotes, leading to mitochondrial damage.


Subject(s)
Leishmania mexicana/drug effects , Trypanocidal Agents/pharmacology , Macrophages/drug effects , Macrophages/parasitology , Salts/pharmacology
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