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1.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199336

RESUMO

The natural compound ravenelin was isolated from the biomass extracts of Exserohilum rostratum fungus, and its antimicrobial, antiplasmodial, and trypanocidal activities were evaluated. Ravenelin was isolated by column chromatography and HPLC and identified by NMR and MS. The susceptibility of Gram-positive and Gram-negative bacteria strains to ravenelin was determined by microbroth dilution assay. Cytotoxicity was evaluated in hepatocarcinoma cells (HepG2) and BALB/c peritoneal macrophages by using MTT. SYBR Green I-based assay was used in the asexual stages of Plasmodium falciparum. Trypanocidal activity was tested against the epimastigote and intracellular amastigote forms of Trypanosoma cruzi. Ravenelin was active against Gram-positive bacteria strains, with emphasis on Bacillus subtilis (MIC value of 7.5 µM). Ravenelin's antiparasitic activities were assessed against both the epimastigote (IC50 value of 5 ± 1 µM) and the intracellular amastigote forms of T. cruzi (IC50 value of 9 ± 2 µM), as well as against P. falciparum (IC50 value of 3.4 ± 0.4 µM). Ravenelin showed low cytotoxic effects on both HepG2 (CC50 > 50 µM) and peritoneal macrophage (CC50 = 185 ± 1 µM) cells with attractive selectivity for the parasites (SI values > 15). These findings indicate that ravenelin is a natural compound with both antibacterial and antiparasitic activities, and considerable selectivity indexes. Therefore, ravenelin is an attractive candidate for hit-to-lead development.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Ascomicetos/química , Macrófagos Peritoneais/citologia , Xantonas/farmacologia , Animais , Antibacterianos/química , Antiprotozoários/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Biomassa , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células Hep G2 , Humanos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Xantonas/química
2.
J Med Chem ; 64(9): 6137-6160, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33945281

RESUMO

Inhibition of Leishmania infantum trypanothione disulfide reductase (LiTryR) by disruption of its homodimeric interface has proved to be an alternative and unexploited strategy in the search for novel antileishmanial agents. Proof of concept was first obtained by peptides and peptidomimetics. Building on previously reported dimerization disruptors containing an imidazole-phenyl-thiazole scaffold, we now report a new 1,2,3-triazole-based chemotype that yields noncompetitive, slow-binding inhibitors of LiTryR. Several compounds bearing (poly)aromatic substituents dramatically improve the ability to disrupt LiTryR dimerization relative to reference imidazoles. Molecular modeling studies identified an almost unexplored hydrophobic region at the interfacial domain as the putative binding site for these compounds. A subsequent structure-based design led to a symmetrical triazole analogue that displayed even more potent inhibitory activity over LiTryR and enhanced leishmanicidal activity. Remarkably, several of these novel triazole-bearing compounds were able to kill both extracellular and intracellular parasites in cell cultures.


Assuntos
Desenho de Fármacos , Leishmania infantum/enzimologia , NADH NADPH Oxirredutases/química , Multimerização Proteica/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Triazóis/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Linhagem Celular , Humanos , Leishmania infantum/efeitos dos fármacos , NADH NADPH Oxirredutases/metabolismo , Estrutura Quaternária de Proteína , Relação Estrutura-Atividade
3.
J Med Chem ; 64(10): 6608-6620, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33974434

RESUMO

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.


Assuntos
Antiprotozoários/química , Complexos de Coordenação/química , Ouro/química , Fosfinas/química , Animais , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Modelos Animais de Doenças , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Parasitária , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trofozoítos/efeitos dos fármacos
4.
J Nat Med ; 75(3): 643-654, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33905079

RESUMO

From the leaves of Ardisia quinquegona, two alkylated tetronic acid derivatives, named ardisiatetrons A and B (1, 2), and four triterpenoids (3-6) were isolated together with one known compound (7) by a combination of various kinds of chromatography. The structure of new methyl migrated triterpene (3) was confirmed by X-ray crystallographic analysis. Compounds 2, 3, and 7 showed moderate anti-Leishmania activity and cytotoxicity towards A549 cells.


Assuntos
Ardisia/química , Furanos/química , Triterpenos/química , Células A549 , Antiprotozoários/química , Humanos , Japão , Leishmania major/efeitos dos fármacos , Estrutura Molecular , Compostos Fitoquímicos/química , Folhas de Planta/química
5.
Molecules ; 26(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801371

RESUMO

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.


Assuntos
Antimaláricos/farmacologia , Antiprotozoários/farmacologia , Cumarínicos/química , Compostos Ferrosos/química , Oxazinas/química , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma brucei brucei/efeitos dos fármacos , Antimaláricos/química , Antiprotozoários/química , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Técnicas In Vitro , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Células Tumorais Cultivadas
6.
J Med Chem ; 64(9): 5905-5930, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33904304

RESUMO

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.


Assuntos
Desenho de Fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Proteínas de Protozoários/metabolismo , Animais , Antiprotozoários/química , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Sítios de Ligação , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/metabolismo , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Camundongos , Simulação de Dinâmica Molecular , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Proteínas de Protozoários/química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade
7.
Molecules ; 26(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917871

RESUMO

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan's cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Quimioinformática , Indazóis/síntese química , Indazóis/farmacologia , Antiprotozoários/química , Entamoeba histolytica/efeitos dos fármacos , Giardia lamblia/efeitos dos fármacos , Indazóis/química , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacos , Ultrassom
8.
Molecules ; 26(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921252

RESUMO

Within this work, we describe the design and synthesis of a range of novel thiochromanones based on natural products reported to possess anti-leishmanial action, and their synthetic derivatives. All compounds were elaborated via the key intermediate 2,2,6-trimethoxythiochromanone, which was modified at the benzylic position to afford various ester, amine and amide analogues, substituted by chains of varying lipophilicity. Upon testing in Leishmania, IC50 values revealed the most potent compounds to be phenylalkenyl and haloalkyl amides 11a and 11e, with IC50 values of 10.5 and 7.2 µM, respectively.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Cromonas/síntese química , Cromonas/farmacologia , Leishmania/efeitos dos fármacos , Animais , Antiprotozoários/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular , Cromonas/química , Camundongos , Testes de Sensibilidade Parasitária
9.
Eur J Med Chem ; 217: 113319, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33725631

RESUMO

The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC50 of 0.24 and 0.25 µM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.


Assuntos
Amidas/farmacologia , Antiprotozoários/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Trypanosoma brucei brucei/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Leucina-tRNA Ligase/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Trypanosoma brucei brucei/enzimologia
10.
Molecules ; 26(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672753

RESUMO

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24-31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4-20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Quinolonas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/química , Staphylococcus aureus/efeitos dos fármacos , Trypanosoma brucei brucei/efeitos dos fármacos
11.
Molecules ; 26(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670791

RESUMO

Betulinic acid (BA, 3ß-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models-with artesunic acid-showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from Betula ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/farmacologia , Antiprotozoários/química , Modelos Moleculares , Triterpenos Pentacíclicos/química , Triterpenos/química
12.
Molecules ; 26(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672916

RESUMO

The in vitro activity of L. donovani (promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells) and T. brucei, from the fractions obtained from the hydroalcoholic extract of the aerial part of Hypericum afrum and the isolated compounds, has been evaluated. The chloroform, ethyl acetate and n-butanol extracts showed significant antitrypanosomal activity towards T. brucei, with IC50 values of 12.35, 13.53 and 12.93 µg/mL and with IC90 values of 14.94, 19.31 and 18.67 µg/mL, respectively. The phytochemical investigation of the fractions led to the isolation and identification of quercetin (1), myricitrin (2), biapigenin (3), myricetin (4), hyperoside (5), myricetin-3-O-ß-d-galactopyranoside (6) and myricetin-3'-O-ß-d-glucopyranoside (7). Myricetin-3'-O-ß-d-glucopyranoside (7) has been isolated for the first time from this genus. The chemical structures were elucidated by using comprehensive one- and two-dimensional nuclear magnetic resonance (1D and 2D NMR) spectroscopic data, as well as high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). These compounds have also been evaluated for their antiprotozoal activity. Quercetin (1) and myricetin (4) showed noteworthy activity against T. brucei, with IC50 and IC90 values of 7.52 and 5.71 µM, and 9.76 and 7.97 µM, respectively. The T. brucei hexokinase (TbHK1) enzyme was further explored as a potential target of quercetin and myricetin, using molecular modeling studies. This proposed mechanism assists in the exploration of new candidates for novel antitrypanosomal drugs.


Assuntos
Antiprotozoários/farmacologia , Flavonoides/farmacologia , Hypericum/química , Modelos Moleculares , Compostos Fitoquímicos/farmacologia , Quercetina/farmacologia , Trypanosoma/efeitos dos fármacos , Sequência de Aminoácidos , Antiprotozoários/química , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Sequência Conservada , Flavonoides/química , Flavonoides/isolamento & purificação , Ligantes , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Estrutura Secundária de Proteína , Proteínas de Protozoários/química , Quercetina/química , Quercetina/isolamento & purificação , Água/química
13.
Molecules ; 26(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525706

RESUMO

Polycyclic endoperoxides are rare natural metabolites found and isolated in plants, fungi, and marine invertebrates. The purpose of this review is a comparative analysis of the pharmacological potential of these natural products. According to PASS (Prediction of Activity Spectra for Substances) estimates, they are more likely to exhibit antiprotozoal and antitumor properties. Some of them are now widely used in clinical medicine. All polycyclic endoperoxides presented in this article demonstrate antiprotozoal activity and can be divided into three groups. The third group includes endoperoxides, which show weak antiprotozoal activity with a reliability of up to 70%, and this group includes only 1.1% of metabolites. The second group includes the largest number of endoperoxides, which are 65% and show average antiprotozoal activity with a confidence level of 70 to 90%. Lastly, the third group includes endoperoxides, which are 33.9% and show strong antiprotozoal activity with a confidence level of 90 to 99.6%. Interestingly, artemisinin and its analogs show strong antiprotozoal activity with 79 to 99.6% confidence against obligate intracellular parasites which belong to the genera Plasmodium, Toxoplasma, Leishmania, and Coccidia. In addition to antiprotozoal activities, polycyclic endoperoxides show antitumor activity in the proportion: 4.6% show weak activity with a reliability of up to 70%, 65.6% show an average activity with a reliability of 70 to 90%, and 29.8% show strong activity with a reliability of 90 to 98.3%. It should also be noted that some polycyclic endoperoxides, in addition to antiprotozoal and antitumor properties, show other strong activities with a confidence level of 90 to 97%. These include antifungal activity against the genera Aspergillus, Candida, and Cryptococcus, as well as anti-inflammatory activity. This review provides insights on further utilization of polycyclic endoperoxides by medicinal chemists, pharmacologists, and the pharmaceutical industry.


Assuntos
Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Produtos Biológicos/farmacologia , Peróxidos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antiprotozoários/química , Produtos Biológicos/química , Humanos , Peróxidos/química
14.
Mar Drugs ; 19(2)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494402

RESUMO

The review of the 2016-2017 marine pharmacology literature was prepared in a manner similar as the 10 prior reviews of this series. Preclinical marine pharmacology research during 2016-2017 assessed 313 marine compounds with novel pharmacology reported by a growing number of investigators from 54 countries. The peer-reviewed literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 123 marine natural products, 111 marine compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 79 marine compounds displayed miscellaneous mechanisms of action which upon further investigation may contribute to several pharmacological classes. Therefore, in 2016-2017, the preclinical marine natural product pharmacology pipeline generated both novel pharmacology as well as potentially new lead compounds for the growing clinical marine pharmaceutical pipeline, and thus sustained with its contributions the global research for novel and effective therapeutic strategies for multiple disease categories.


Assuntos
Organismos Aquáticos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Sistema Imunitário/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Antituberculosos/química , Antituberculosos/isolamento & purificação , Antituberculosos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacologia , Organismos Aquáticos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Sistema Imunitário/fisiologia , Fenômenos Farmacológicos e Toxicológicos
15.
Chem Biol Interact ; 336: 109389, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33484715

RESUMO

Leishmaniases are infectious diseases caused by protozoa of the genus Leishmania, that may have different clinical manifestations. First line drugs used in the treatment of leishmaniosis are high costly, and are very aggressive requiring medical monitoring. Thus new therapeutic alternatives are needed and, in this context, natural products have been considered as a source of new antileishmania agents. Riparins are alkamides found in the unripe fruits of Aniba riparia. Several biological activities are described for this group of compounds, such as antimicrobial and antiparasitic potential. The objective of this work was to evaluate the anti-leishmania activity riparin E (Rip-E) in vitro, against promastigotes and internalized amastigotes of Leishmania amazonensis. Rip-E was able to inhibit promastigote cell growth (IC50 4.7 µg/ml) and to reduce the percentage of macrophages infected with amastigotes, reducing its infectivity (survival index) (IC50 1.3 µg/ml). The cytotoxicity against BALB/c murine macrophages was also assessed (CC50 50.6 µg/ml) and the selectivity index was 38.9. Rip-E also demonstrated immunomodulatory activity, evidenced by the increase of the phagocytic capacity and lysosomal activity. However, Rip-E did not affect directly the production of nitric oxide. These results suggest that Rip-E has antileishmania potential, by both its direct inhibitory effect and its ability to activate macrophages.


Assuntos
Antiprotozoários/farmacologia , Imunomodulação , Leishmania/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Proliferação de Células/efeitos dos fármacos , Feminino , Leishmania/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária
16.
Molecules ; 26(3)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33504100

RESUMO

Thiazole, a five-membered heteroaromatic ring, is an important scaffold of a large number of synthetic compounds. Its diverse pharmacological activity is reflected in many clinically approved thiazole-containing molecules, with an extensive range of biological activities, such as antibacterial, antifungal, antiviral, antihelmintic, antitumor, and anti-inflammatory effects. Due to its significance in the field of medicinal chemistry, numerous biologically active thiazole and bisthiazole derivatives have been reported in the scientific literature. The current review provides an overview of different methods for the synthesis of thiazole and bisthiazole derivatives and describes various compounds bearing a thiazole and bisthiazole moiety possessing antibacterial, antifungal, antiprotozoal, and antitumor activity, encouraging further research on the discovery of thiazole-containing drugs.


Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Antiprotozoários/química , Tiazóis/química , Animais , Anti-Infecciosos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Humanos , Tiazóis/farmacologia
17.
Molecules ; 26(3)2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498621

RESUMO

In the course of our studies on antiprotozoal natural products and following our recent discovery that certain aminosteroids and aminocycloartanoid compounds from Holarrhena africana A. DC. (Apocynaceae) and Buxus sempervirens L. (Buxaceae), respectively, are strong and selective antitrypanosomal agents, we have extended these studies to another plant, related to the latter-namely, Pachysandra terminalis Sieb. and Zucc. (Buxaceae). This species is known to contain aminosteroids similar to those of Holarrhena and structurally related to the aminocycloartanoids of Buxus. The dicholoromethane extract obtained from aerial parts of P. terminalis and, in particular, its alkaloid fraction obtained by acid-base partitioning showed prominent activity against Trypanosoma brucei rhodesiense (Tbr). Activity-guided fractionation along with extended UHPLC-(+)ESI QTOF MS analyses coupled with partial least squares (PLS) regression modelling relating the analytical profiles of various fractions with their bioactivity against Tbr highlighted eighteen constituents likely responsible for the antitrypanosomal activity. Detailed analysis of their (+)ESI mass spectral fragmentation allowed identification of four known constituents of P. terminalis as well as structural characterization of ten further amino-/amidosteroids not previously reported from this plant.


Assuntos
Alcaloides/química , Buxaceae/química , Pachysandra/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Trypanosoma brucei rhodesiense/química , Antiprotozoários/química , Apocynaceae/química , Buxus/química , Holarrhena/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia
18.
Eur J Med Chem ; 212: 113101, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33385837

RESUMO

The kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are the causative agents of neglected tropical diseases with a serious burden in several parts of the world. These parasites are incapable of synthesizing purines de novo, and therefore rely on ingenious purine salvage pathways to acquire and process purines from their host. Purine nucleoside analogs that may interfere with these pathways therefore constitute a privileged source of new antikinetoplastid agents. In this study, we synthetized a collection of C-nucleosides employing five different heterocyclic nucleobase surrogates. C-nucleosides are chemically and enzymatically stable and allow for extensive structural modification. Inspired by earlier 7-deazaadenosine nucleosides and known antileishmanial C-nucleosides, we introduced different modifications tailored towards antikinetoplastid activity. Both adenosine and inosine analogs were synthesized with the aim of discovering new antikinetoplastid hits and expanding knowledge of structure-activity relationships. Several promising hits with potent activity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum were discovered, and the nature of the nucleobase surrogate was found to have a profound influence on the selectivity profile of the compounds.


Assuntos
Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Nucleosídeos/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
19.
Chem Biodivers ; 18(1): e2000839, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33231345

RESUMO

New pyranonaphthoquinone derivatives were synthesized and investigated for their activity against Trypanosoma brucei, Leishmania major, and Toxoplasma gondii parasites. The pentafluorophenyl derivative was efficacious against T. brucei with single digit micromolar EC50 values and against T. gondii with even sub-micromolar values. The 3-chloro-4,5-dimethoxyphenyl derivative showed an activity against amastigotes of Leishmania major parasites comparable to that of amphotericin B. In addition, antioxidant activities were observed for the bromophenyl derivatives, and their redox behavior was studied by cyclovoltammetry. Anti-parasitic and antioxidative activities of the new naphthoquinone derivatives appear uncorrelated.


Assuntos
Antiprotozoários/química , Benzopiranos/química , Animais , Antioxidantes , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Benzopiranos/farmacologia , Humanos , Leishmania major/efeitos dos fármacos , Naftoquinonas/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
20.
Eur J Med Chem ; 210: 112994, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33234343

RESUMO

Nitroimidazoles based compounds remain a hot topic of research in medicinal chemistry due to their numerous biological activities. Moreover, many clinical candidates based on this chemical core have been reported to be valuable in the treatment of human diseases. Metronidazole (MTZ) derived conjugates demonstrated a potential application in medicinal chemistry research over the last decade. In this review, we summarize the synthesis, key structure-activity-relationship (SAR) and associated biological activities such as antimicrobial, anticancer, antidiabetic, anti-inflammatory, anti-HIV and anti-parasitic (Anti-trichomonas, antileishmanial, antiamoebic and anti-giardial) of explored MTZ-conjugates. The molecular docking analysis is also presented simultaneously, which will assist in developing an understanding towards designing of new MTZ-conjugates for target-based drug discovery against multiple disease areas.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Hipoglicemiantes/farmacologia , Metronidazol/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Desenvolvimento de Medicamentos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Metronidazol/síntese química , Metronidazol/química
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