RESUMO
The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1-2 µM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. The results were corroborated with computational docking studies. Arguably, the synthetic proline amides represent the structurally simplest examples of in vitro pan antiprotozoal compounds.
Assuntos
Captopril , Trypanosoma brucei brucei , Trypanosoma cruzi , Captopril/farmacologia , Captopril/química , Captopril/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/enzimologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Estrutura Molecular , Leishmania/efeitos dos fármacos , Leishmania/enzimologia , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , HumanosRESUMO
In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.
Assuntos
Benzimidazóis , Hidrazonas , Leishmania infantum , Trypanosoma cruzi , Trypanosoma cruzi/efeitos dos fármacos , Hidrazonas/farmacologia , Hidrazonas/química , Hidrazonas/síntese química , Relação Estrutura-Atividade , Leishmania infantum/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/química , Benzimidazóis/síntese química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Dose-Resposta a Droga , Leishmania/efeitos dos fármacos , Tripanossomicidas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/química , Antiprotozoários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , AnimaisRESUMO
Leishmaniasis and Chagas disease are neglected tropical diseases caused by Trypanosomatidae parasites. Given the numerous limitations associated with current treatments, such as extended treatment duration, variable efficacy, and severe side effects, there is an urgent imperative to explore novel therapeutic options. This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in the fight against Chagas disease and leishmaniasis.
Assuntos
Desenho de Fármacos , Leishmania infantum , Testes de Sensibilidade Parasitária , Trypanosoma cruzi , Trypanosoma cruzi/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Tripanossomicidas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/química , Relação Dose-Resposta a Droga , Antiprotozoários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Humanos , Animais , Sulfonas/farmacologia , Sulfonas/síntese química , Sulfonas/químicaRESUMO
Species of Leishmania and Trypanosoma genera are the causative agents of relevant parasitic diseases. Survival inside their hosts requires the existence of a potent antioxidant enzymatic machinery. Four iron superoxide dismutases have been described in trypanosomatids (FeSODA, FeSODB1, FeSODB2, and FeSODC) that hold a potential as therapeutic targets. Nonetheless, very few studies have been developed that make use of the purified enzymes. Moreover, FeSODC remains uncharacterised in Leishmania. In this work, for the first time, we describe the purification and enzymatic activity of recombinant versions of the four Leishmania FeSOD isoforms and establish an improved strategy for developing inhibitors. We propose a novel parameter [(V*cyt. c - Vcyt. c)/Vcyt. c] which, in contrast to that used in the classical cytochrome c reduction assay, correlates linearly with enzyme concentration. As a proof of concept, we determine the IC50 values of two ruthenium carbosilane metallodendrimers against these isoforms.
Assuntos
Antiprotozoários , Relação Dose-Resposta a Droga , Leishmania infantum , Testes de Sensibilidade Parasitária , Superóxido Dismutase , Leishmania infantum/enzimologia , Leishmania infantum/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Superóxido Dismutase/metabolismo , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/química , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologiaRESUMO
Managing primary amoebic meningoencephalitis, induced by Naegleria fowleri poses a complex medical challenge. There is currently no specific anti-amoebic drug that has proven effectiveness against N. fowleri infection. Ongoing research endeavours are dedicated to uncovering innovative treatment strategies, including the utilization of drugs and immune modulators targeting Naegleria infection. In this study, we explored the potential of imidazo[2,1-b]thiazole and imidazooxazole derivatives that incorporate sulfonate and sulfamate groups as agents with anti-amoebic properties against N. fowleri. We assessed several synthesized compounds (1f, 1m, 1q, 1s, and 1t) for their efficacy in eliminating amoebae, their impact on cytotoxicity, and their influence on the damage caused to human cerebral microvascular endothelial (HBEC-5i) cells when exposed to the N. fowleri (ATCC 30174) strain. The outcomes revealed that, among the five compounds under examination, 1m, 1q, and 1t demonstrated notable anti-parasitic effects against N. fowleri (P ≤ 0.05). Compound 1t exhibited the highest anti-parasitic activity, reducing N. fowleri population by 80%. Additionally, three compounds, 1m, 1q, and 1t, significantly mitigated the damage inflicted on host cells by N. fowleri. However, the results of cytotoxicity analysis indicated that while 1m and 1q had minimal cytotoxic effects on endothelial cells, compound 1t caused moderate cytotoxicity (34%). Consequently, we conclude that imidazo[2,1-b]thiazole and imidazooxazole derivatives containing sulfonate and sulfamate groups exhibit a marked capacity to eliminate amoebae viability while causing limited toxicity to human cells. In aggregate, these findings hold promise that could potentially evolve into novel therapeutic options for treating N. fowleri infection.
Assuntos
Antiprotozoários , Células Endoteliais , Naegleria fowleri , Tiazóis , Humanos , Tiazóis/farmacologia , Tiazóis/química , Naegleria fowleri/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Linhagem Celular , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Oxazóis/farmacologia , Oxazóis/química , Sobrevivência Celular/efeitos dos fármacosRESUMO
In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.
Assuntos
Desenho de Fármacos , Hidrazinas , Leishmania , Naftoquinonas , Tripanossomicidas , Trypanosoma cruzi , Naftoquinonas/farmacologia , Naftoquinonas/química , Naftoquinonas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Tripanossomicidas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/química , Leishmania/efeitos dos fármacos , Hidrazinas/química , Hidrazinas/farmacologia , Animais , Antiprotozoários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Testes de Sensibilidade Parasitária , Concentração Inibidora 50 , Relação Estrutura-Atividade , Cisteína EndopeptidasesRESUMO
We have evaluated eight p-coumaric acid prenylated derivatives inâ vitro for their antileishmanial activity against Leishmania amazonensis promastigotes and their antischistosomal activity against Schistosoma mansoni adult worms. Compound 7 ((E)-3,4-diprenyl-4-isoprenyloxycinnamic alcohol) was the most active against L. amazonensis (IC50=45.92â µM) and S. mansoni (IC50=64.25â µM). Data indicated that the number of prenyl groups, the presence of hydroxyl at C9, and a single bond between C7 and C8 are important structural features for the antileishmanial activity of p-coumaric acid prenylated derivatives.
Assuntos
Antiprotozoários , Ácidos Cumáricos , Leishmania , Testes de Sensibilidade Parasitária , Schistosoma mansoni , Animais , Schistosoma mansoni/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Ácidos Cumáricos/química , Leishmania/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Relação Estrutura-Atividade , Prenilação , Propionatos/farmacologia , Propionatos/química , Estrutura Molecular , Esquistossomicidas/farmacologia , Esquistossomicidas/química , Esquistossomicidas/síntese química , Relação Dose-Resposta a DrogaRESUMO
Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for sleeping sickness (Trypanosoma brucei rhodesiense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half-maximal effective concentration (EC50) values of 0.68, 0.8, and 0.19 µM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages (â¼100-fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC50 values of 1.4 and 0.4 µM, respectively.
Assuntos
Antiprotozoários , Leishmania infantum , Testes de Sensibilidade Parasitária , Quinolinas , Trypanosoma brucei rhodesiense , Trypanosoma cruzi , Animais , Camundongos , Quinolinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Humanos , Relação Estrutura-Atividade , Leishmania infantum/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Estrutura Molecular , Trypanosoma brucei brucei/efeitos dos fármacos , Relação Dose-Resposta a Droga , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Fibroblastos/efeitos dos fármacosRESUMO
Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound 26/HIT 8. We previously identified this molecule as a 'hit' during a high-throughput screening campaign for autophagy inducers. A variety of synthetic strategies were utilized to modify the 1,3-diarylpyrazole core at its 1-, 3-, and 4-position. Compounds were assessed in vitro to identify their cytotoxicity properties. Of note, several compounds in the series displayed relevant cytotoxicity, which warrants scrutiny while interpreting biological activities that have been reported for structurally related molecules. In addition, antiparasitic activities were recorded against a range of human-infective protozoa, including Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania infantum. The most interesting compounds displayed low micromolar whole-cell potencies against individual or several parasitic species, while lacking cytotoxicity against human cells.
Assuntos
Pirazóis , Trypanosoma cruzi , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Humanos , Trypanosoma cruzi/efeitos dos fármacos , Antiparasitários/farmacologia , Antiparasitários/síntese química , Antiparasitários/química , Desenho de Fármacos , Leishmania infantum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/químicaRESUMO
Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the meso, 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against Trypanosoma brucei and Leishmania major parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the meso-substituted BODIPY, with 1-dimethylaminonaphthalene (1b) and anthracene moiety (1c), were the most active against L. major, displaying IC50 = 4.84 and 5.41 µM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues 2b and 2c exhibited the highest toxicity (IC50 = 2.84 and 6.17 µM, respectively) and selectivity (SI = 24 and 11, respectively) against T. brucei. Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP+ linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.
Assuntos
Antiprotozoários , Compostos de Boro , Leishmania major , Simulação de Acoplamento Molecular , Trypanosoma brucei brucei , Compostos de Boro/química , Compostos de Boro/farmacologia , Compostos de Boro/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Humanos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Leishmania major/efeitos dos fármacos , Desenho de Fármacos , Relação Estrutura-Atividade , Linhagem Celular , Estrutura Molecular , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , OxirredutasesRESUMO
Neglected tropical diseases (NTDs) comprise diverse infections with more incidence in tropical/sub-tropical areas. In spite of preventive and therapeutic achievements, NTDs are yet serious threats to the public health. Epidemiological reports of world health organization (WHO) indicate that more than 1.5 billion people are afflicted with at least one NTD type. Among NTDs, leishmaniasis, chagas disease (CD) and human African trypanosomiasis (HAT) result in substantial morbidity and death, particularly within impoverished countries. The statistical facts call for robust efforts to manage the NTDs. Currently, most of the anti-NTD drugs are engaged with drug resistance, lack of efficient vaccines, limited spectrum of pharmacological effect and adverse reactions. To circumvent the issue, numerous scientific efforts have been directed to the synthesis and pharmacological development of chemical compounds as anti-infectious agents. A survey of the anti-NTD agents reveals that the majority of them possess privileged nitrogen, sulfur and oxygen-based heterocyclic structures. In this review, recent achievements in anti-infective small molecules against parasitic NTDs are described, particularly from the SAR (Structure activity relationship) perspective. We also explore current advocating strategies to extend the scope of anti-NTD agents.
Assuntos
Doenças Negligenciadas , Doenças Negligenciadas/tratamento farmacológico , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Doença de Chagas/tratamento farmacológico , Leishmaniose/tratamento farmacológico , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Testes de Sensibilidade Parasitária , Medicina TropicalRESUMO
Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 µM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.
Assuntos
Antiprotozoários , Benzotiazóis , Hidrazonas , Leishmania , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzotiazóis/síntese química , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Animais , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Camundongos , Leishmania/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Relação Estrutura-Atividade , HumanosRESUMO
Acanthamoeba are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis, which is generally fatal. The development of efficient and safe drugs is a critical unmet need. Acanthamoeba sterol 14α-demethylase (CYP51) is an essential enzyme of the sterol biosynthetic pathway. Repurposing antifungal azoles for amoebic infections has been reported, but their inhibitory effects on Acanthamoeba CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from Acanthamoeba castellanii. The enzyme displays a 100-fold substrate preference for obtusifoliol over lanosterol, supporting the plant-like cycloartenol-based pathway in the pathogen. The strongest inhibition was observed with voriconazole (1 h IC50 0.45 µM), VT1598 (0.25 µM), and VT1161 (0.20 µM). The crystal structures of A. castellanii CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness.
Assuntos
Inibidores de 14-alfa Desmetilase , Esterol 14-Desmetilase , Esterol 14-Desmetilase/metabolismo , Esterol 14-Desmetilase/química , Inibidores de 14-alfa Desmetilase/farmacologia , Inibidores de 14-alfa Desmetilase/química , Inibidores de 14-alfa Desmetilase/síntese química , Relação Estrutura-Atividade , Acanthamoeba/enzimologia , Acanthamoeba/efeitos dos fármacos , Acanthamoeba castellanii/enzimologia , Acanthamoeba castellanii/efeitos dos fármacos , Cristalografia por Raios X , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Modelos Moleculares , Estrutura MolecularRESUMO
Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC50 value against the parasite (1.10â µg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1's putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1â µM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1-compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds.
Assuntos
Acridinas , Inibidores Enzimáticos , Oxirredutases , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Acridinas/química , Acridinas/farmacologia , Acridinas/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Simulação de Dinâmica Molecular , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Compostos de Espiro/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Dose-Resposta a Droga , Leishmania/efeitos dos fármacos , Leishmania/enzimologia , Simulação de Acoplamento MolecularRESUMO
Neglected tropical diseases (NTDs) pose a major threat in tropical zones for impoverished populations. Difficulty of access, adverse effects or low efficacy limit the use of current therapeutic options. Therefore, development of new drugs against NTDs is a necessity. Compounds containing an aminopyridine (AP) moiety are of great interest for the design of new anti-NTD drugs due to their intrinsic properties compared with their closest chemical structures. Currently, over 40 compounds with an AP moiety are on the market, but none is used against NTDs despite active research on APs. The aim of this review is to present the medicinal chemistry work carried out with these scaffolds, against protozoan NTDs: Trypanosoma cruzi, Trypanosoma brucei or Leishmania spp.
[Box: see text].
Assuntos
Aminopiridinas , Antiprotozoários , Doenças Negligenciadas , Trypanosoma brucei brucei , Trypanosoma cruzi , Doenças Negligenciadas/tratamento farmacológico , Humanos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Aminopiridinas/química , Aminopiridinas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Desenvolvimento de Medicamentos , Testes de Sensibilidade Parasitária , AnimaisRESUMO
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.
Assuntos
Antiprotozoários , Leishmania donovani , Leishmania mexicana , Animais , Relação Estrutura-Atividade , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/uso terapêutico , Antiprotozoários/síntese química , Antiprotozoários/farmacocinética , Camundongos , Leishmania donovani/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Descoberta de Drogas , Humanos , Feminino , Leishmaniose/tratamento farmacológico , Camundongos Endogâmicos BALB CRESUMO
Three types of modifications of antileishmanial pyrazole lead compounds 7 and 8 were conducted to expand understanding of the relationships between structural features and antileishmanial/antitrypanosomal activity: (1) the pyrazole core was retained or replaced by a 1,2,4-triazole ring; (2) various aryl moieties including 2-fluorophenyl, pyridin-3-yl and pyrazin-2-yl rings were attached at 3-position of the core azole; (3) either arylmethylamino or ureido substituents were introduced at 5-position of the azole core. The synthesis followed established routes starting with esters 9 or 15 and anhydride 21. The synthesized 3-arylpyrazoles and 3-aryl-1,2,4-triazoles had only very low antileishmanial activity. The 2-fluorophenyl-substituted pyrazole 18c revealed the highest antileishmanial activity of this series of compounds, but its IC50 value (20â µM) still indicates low activity. However, low micromolar antitrypanosomal activity was detected for the pyridin-3-yl-substituted pyrazoles 12b (IC50=4.7â µM) and 14a (IC50=2.1â µM). Their IC50 values are comparable with the IC50 values of the reference compounds benznidazole and nifurtimox. Whereas only low unspecific cytotoxicity at the primary peritoneal mouse macrophages (PMM) was detected, considerable cytotoxicity at MRC-5 human fibroblast cells was found for both pyrazoles 12b an 14a. The activity of pyrazole 12b against T. cruzi is 4-fold higher than its unspecific MRC-5 cytotoxicity.
Assuntos
Pirazóis , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Relação Estrutura-Atividade , Animais , Camundongos , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Ureia/farmacologia , Ureia/química , Ureia/análogos & derivados , Ureia/síntese química , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Estrutura Molecular , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Humanos , Testes de Sensibilidade Parasitária , Relação Dose-Resposta a Droga , Linhagem CelularRESUMO
A thiophene-derived Schiff base ligand (E)-2-morpholino-N-(thiophen-2-ylmethylene)ethanamine was used for the synthesis of M(II) complexes, [TEM(M)X2] (M = Co, Cu, Zn; X = Cl; M = Cd, X = Br). Structural characterization of the synthesized complexes revealed distorted tetrahedral geometry around the M(II) center. In vitro investigation of the synthesized ligand and its M(II) complexes showed considerable anti-urease and leishmanicidal potential. The synthesized complexes also exhibited a significant inhibitory effect on urease, with IC50 values in the range of 3.50-8.05 µM. In addition, the docking results were consistent with the experimental results. A preliminary study of human colorectal cancer (HCT), hepatic cancer (HepG2), and breast cancer (MCF-7) cell lines showed marked anticancer activities of these complexes.
Assuntos
Antineoplásicos , Complexos de Coordenação , Simulação de Acoplamento Molecular , Bases de Schiff , Tiofenos , Urease , Humanos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Urease/antagonistas & inibidores , Urease/metabolismo , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química , Morfolinas/química , Morfolinas/farmacologia , Morfolinas/síntese química , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Leishmania/efeitos dos fármacos , Relação Estrutura-Atividade , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
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Assuntos
Humanos , Antiprotozoários/farmacologia , Leishmania guyanensis/efeitos dos fármacos , Quinolinas/farmacologia , Estirenos/farmacologia , /efeitos dos fármacos , Antiprotozoários/química , Antiprotozoários/síntese química , Antiprotozoários/toxicidade , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Quinolinas/química , Quinolinas/síntese química , Quinolinas/toxicidade , Estirenos/química , Estirenos/síntese química , Estirenos/toxicidadeRESUMO
A series of seven limonene β-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene β-amino alcohol derivatives.