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1.
PLoS One ; 15(5): e0225232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442170

RESUMO

Toxoplasma gondii is the etiologic agent of toxoplasmosis, a disease which can lead to morbidity and mortality of the fetus and immunocompromised individuals. Due to the limited effectiveness or side effects of existing drugs, the search for better drug candidates is still ongoing. In this study, we performed structure-based screening of potential dual-targets inhibitors of active sites of T. gondii drug targets such as uracil phosphoribosyltransferase (UPRTase) and adenosine kinase (AK). First screening of virtual compounds from the National Cancer Institute (NCI) was performed via molecular docking. Subsequently, the hit compounds were tested in-vitro for anti- T. gondii effect using cell viability assay with Vero cells as host to determine cytotoxicity effects and drug selectivities. Clindamycin, as positive control, showed a selectivity index (SI) of 10.9, thus compounds with SI > 10.9 specifically target T. gondii proliferation with no significant effect on the host cells. Good anti- T. gondii effects were observed with NSC77468 (7-ethoxy-4-methyl-6,7-dihydro-5H-thiopyrano[2,3-d]pyrimidin-2-amine) which showed SI values of 25. This study showed that in-silico selection can serve as an effective way to discover potentially potent and selective compounds against T. gondii.


Assuntos
Adenosina Quinase/antagonistas & inibidores , Antiprotozoários/farmacologia , Pentosiltransferases/antagonistas & inibidores , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Animais , Antiprotozoários/química , Chlorocebus aethiops , Relação Estrutura-Atividade , Células Vero
2.
Parasitol Res ; 119(7): 2263-2274, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32462293

RESUMO

Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which makes the development of new drugs urgent. To achieve this goal, the integration of kinetic and DSF assays against parasitic validated targets, along with phenotypic assays, can help the identification and optimization of bioactive compounds. Pteridine reductase 1 (PTR1), a validated target in Leishmania sp., is responsible for the reduction of folate and biopterin to tetrahydrofolate and tetrahydrobiopterin, respectively, both of which are essential for cell growth. In addition to the in vitro evaluation of 16 thiazolidine-2,4-dione derivatives against Leishmania major PTR1 (LmPTR1), using the differential scanning fluorimetry (ThermoFluor®), phenotypic assays were employed to evaluate the compound effect over Leishmania braziliensis (MHOM/BR/75/M2903) and Leishmania infantum (MHOM/BR/74/PP75) promastigotes viability. The ThermoFluor® results show that thiazolidine-2,4-dione derivatives have micromolar affinity to the target and equivalent activity on Leishmania cells. 2b is the most potent compound against L. infantum (EC50 = 23.45 ± 4.54 µM), whereas 2a is the most potent against L. braziliensis (EC50 = 44.16 ± 5.77 µM). This result suggests that lipophilic substituents on either-meta and/or-para positions of the benzylidene ring increase the potency against L. infantum. On the other hand, compound 2c (CE50 = 49.22 ± 7.71 µM) presented the highest selectivity index.


Assuntos
Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Antiprotozoários/química , Humanos , Leishmania braziliensis/enzimologia , Leishmania infantum/enzimologia , Oxirredutases/antagonistas & inibidores , Testes de Sensibilidade Parasitária , Tiazolidinedionas/química
3.
Chem Biol Interact ; 320: 109026, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112863

RESUMO

Leishmaniasis is a widespread tropical infection caused by different species of Leishmania protozoa. Many of the available drugs against the disease are toxic and in certain cases parasite drug resistance is developed. The discovery of drugs for the treatment of leishmaniasis is a pressing concern. In the present work, we describe in vitro studies of the phenolic compound methyl gallate (MG) against Leishmania (Leishmania) amazonensis and its possible mechanisms of action. The in vitro activity of MG was assayed against L. amazonensis (promastigotes, axenic amastigotes, and intramacrophagic amastigotes). Cytotoxicity tests were performed with J774A.1 macrophages and THP-1 cell derived macrophages. To evaluate mechanisms of action, we analyzed cellular TNF-α, IL-12, IFN-γ, IL-10, IL-6, NO, ROS levels, arginase activity, and structural mechanisms (phagocytic and lysosomal activities) involving macrophage activation. Meglumine antimoniate and amphotericin B were used as reference drugs. It was observed that MG effectively inhibited the growth of both promastigote (IC50 5.71 µM) and amastigote-like forms (EC50 5.39 µM), with much higher selectivity indexes than the reference drugs, being more benign towards J774A.1 macrophages than meglumine antimoniate and amphotericin B, at 1631- and 70.92-fold respectively, with respect to the promastigote form. Additionally, MG proved to be even more active against intracellular amastigotes of the parasite (EC50 4.24 µM). Our results showed that antileishmania activity was associated with increased TNF-α, IL-12, NO and ROS levels, as well as decreased IL-6 and decreased arginase activity. In addition, MG induced increased phagocytic capability, and lysosomal volume in macrophages; structural parameters of microbicidal activity. Taken together, our results suggest that MG may be a promising candidate for new drug development against leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Ácido Gálico/análogos & derivados , Leishmania/efeitos dos fármacos , Anfotericina B/farmacologia , Antiprotozoários/química , Ácido Gálico/efeitos adversos , Ácido Gálico/química , Ácido Gálico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Antimoniato de Meglumina/farmacologia , Estrutura Molecular , Espécies Reativas de Oxigênio
4.
BMC Complement Med Ther ; 20(1): 87, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183812

RESUMO

BACKGROUND: The antiprotozoal and antioxidant activities of Viola tricolor and Laurus nobilis have been reported recently. Thus, the existing study pursued to assess the growth inhibition effect of methanolic extract of V. tricolor (MEVT) and acetonic extract of L. nobilis (AELN) against five Babesia parasites and Theileria equi in vitro and in vivo. RESULTS: MEVT and AELN suppressed Babesia bovis, B. bigemina, B. divergens, B. caballi, and T. equi growth at half-maximal inhibitory concentration (IC50) values of 75.7 ± 2.6, 43.3 ± 1.8, 67.6 ± 2.8, 48 ± 3.8, 54 ± 2.1 µg/mL, and 86.6 ± 8.2, 33.3 ± 5.1, 62.2 ± 3.3, 34.5 ± 7.5 and 82.2 ± 9.3 µg/mL, respectively. Qualitative phytochemical estimation revealed that both extracts containing multiple bioactive constituents and significant amounts of flavonoids and phenols. The toxicity assay revealed that MEVT and AELN affected the mouse embryonic fibroblast (NIH/3 T3) and Madin-Darby bovine kidney (MDBK) cell viability with half-maximum effective concentrations (EC50) of 930 ± 29.9, 1260 ± 18.9 µg/mL, and 573.7 ± 12.4, 831 ± 19.9 µg/mL, respectively, while human foreskin fibroblasts (HFF) cell viability was not influenced even at 1500 µg/mL. The in vivo experiment revealed that the oral administration of MEVT and AELN prohibited B. microti multiplication in mice by 35.1 and 56.1%, respectively. CONCLUSIONS: These analyses indicate the prospects of MEVT and AELN as good candidates for isolating new anti-protozoal compounds which could assist in the development of new drug molecules with new drug targets.


Assuntos
Antiprotozoários/farmacologia , Babesia/efeitos dos fármacos , Laurus/química , Extratos Vegetais/farmacologia , Theileria/efeitos dos fármacos , Viola/química , Acetona , Antiprotozoários/química , Cromatografia Gasosa-Espectrometria de Massas , Metanol , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química
5.
Org Biomol Chem ; 18(7): 1462-1475, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32025679

RESUMO

Selective glycosylation of the C-6 fluorinated galactofuranosyl acceptor 2 was studied with four galactofuranosyl donors. It was highlighted that this electron-withdrawing atom strongly impacted the behavior of the acceptor, thus leading to unprecedented glycosylation pathways. Competition between expected glycosylation of 2, ring expansion of this acceptor and furanosylation, and intermolecular aglycon transfer was observed. Further investigation of the fluorinated synthetic compounds showed that the presence of fluorine atom contributed to increase the inhibition of the growth of Leishmania tarentolae, a non-pathogenic strain of Leishmania.


Assuntos
Antiprotozoários/farmacologia , Furanos/farmacologia , Galactosídeos/farmacologia , Leishmania/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Configuração de Carboidratos , Furanos/síntese química , Furanos/química , Galactosídeos/síntese química , Galactosídeos/química , Glicosilação , Testes de Sensibilidade Parasitária , Estereoisomerismo
6.
Mem Inst Oswaldo Cruz ; 115: e190348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049098

RESUMO

BACKGROUND: It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES: To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS: CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20: showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS: The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.


Assuntos
Albendazol/farmacologia , Antiprotozoários/farmacologia , Proteínas do Citoesqueleto/efeitos dos fármacos , Giardia lamblia/efeitos dos fármacos , Tiazóis/farmacologia , Albendazol/química , Animais , Antiprotozoários/química , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Camundongos , Testes de Sensibilidade Parasitária , Tiazóis/química , Fatores de Tempo
7.
PLoS Negl Trop Dis ; 14(2): e0007983, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32106219

RESUMO

The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including base pairs and base mis-pairs, that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase (aaRS) interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. We also identified Leishmania major threonyl-tRNA synthetase (ThrRS) inhibitors from the same library. We discuss why chemotherapies targeting multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS.


Assuntos
Alanina-tRNA Ligase/antagonistas & inibidores , Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Leishmania/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Treonina-tRNA Ligase/antagonistas & inibidores , Trypanosoma/efeitos dos fármacos , Alanina-tRNA Ligase/genética , Alanina-tRNA Ligase/metabolismo , Antiprotozoários/química , Inibidores Enzimáticos/química , Humanos , Leishmania/efeitos dos fármacos , Leishmania/genética , Leishmaniose/parasitologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Treonina-tRNA Ligase/genética , Treonina-tRNA Ligase/metabolismo , Trypanosoma/enzimologia , Trypanosoma/genética , Tripanossomíase/parasitologia
8.
J Enzyme Inhib Med Chem ; 35(1): 432-459, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899980

RESUMO

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Desenho de Fármacos , Quinolinas/química , Quinolinas/farmacologia , Antiprotozoários/síntese química , Células Hep G2 , Humanos , Leishmania donovani/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/síntese química , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacos
9.
Carbohydr Polym ; 232: 115826, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952620

RESUMO

The study investigated chitosan coated nanostructured lipid carriers (NLCs) for oral delivery of albendazole in treatment of trichinellosis. NLCs comprised precirol and oleic acid with Tween and Span 80. Dicetylphosphate was used as charging agent to allow chitosan coating. Trichinella spiralis infected mice were used and albendazole suspension, coated or uncoated NLCs were orally administered at different stages of infection. NLCs were spherical with size of 188 and 200 nm for coated and uncoated NLC, respectively. Treatment during intestinal phase reduced worm count with NLCs showing better rank. This was reflected further by reduced larvae count and improved histopathological features. Starting treatment in the migrating phase reduced larval count by 62.9, 99.6 and 89.5 % after administration of suspension, coated and uncoated NLCs, respectively. The same rank was recorded for the encysted phase. NLCs enhanced the efficacy of albendazole against Trichinella spiralis compared with suspension with chitosan coated NLCs being superior.


Assuntos
Albendazol/farmacologia , Antiprotozoários/farmacologia , Quitosana/química , Lipídeos/química , Nanoestruturas/química , Trichinella spiralis/efeitos dos fármacos , Administração Oral , Albendazol/administração & dosagem , Albendazol/química , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Lipídeos/administração & dosagem , Nanoestruturas/administração & dosagem , Testes de Sensibilidade Parasitária , Tamanho da Partícula , Propriedades de Superfície
10.
Eur J Med Chem ; 186: 111895, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771825

RESUMO

A series of eight alkyl gallium complexes of general formulae [GaMe2(L)] and [Ga(Me)2L] have been synthesised, characterised and their antimicrobial activity against bacteria, cancer cells and Leishmania assessed. All eight complexes are novel, with the solid-state structures of all complexes successfully authenticated by single crystal X-ray diffraction. The dimethyl complexes all adopt a four-coordinate tetrahedral confirmation, while the monomethyl complexes are five-coordinate trigonal bipyramidal. All complexes were screened for their anti-bacterial activity either by solution state diffusion, or a solid-state stab test. The five soluble complexes underwent testing against two differing mammalian cell controls, with excellent selectivity observed against COS-7 cells, with an IC50 range of 88.5 µM to ≥100 µM. Each soluble complex was also tested for their anti-cancer capabilities, with no significant activity observed. Excellent activity was exhibited against the protozoan parasite Leishmania major (strain: V121) in both the promastigote and amastigote forms, with IC50 values ranging from 1.11 µM-13.4 µM for their anti-promastigote activity and % infection values of 3.5% ± 0.65-11.5% ± 0.65 for the more clinically relevant amastigote. Selectivity indices for each were found to be in the ranges of 6.61-64.7, with significant selectivity noted for two of the complexes. At minimum, the gallium complexes show a 3-fold enhancement in activity towards the Leishmaniaamastigotes over the parent quinolinols alone.


Assuntos
Antiprotozoários/farmacologia , Complexos de Coordenação/farmacologia , Gálio/farmacologia , Hidroxiquinolinas/farmacologia , Leishmania major/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Células COS , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Gálio/química , Células HeLa , Humanos , Hidroxiquinolinas/química , Leishmania major/metabolismo , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/análise , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 186: 111887, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787363

RESUMO

The current treatment of Chagas disease is based on the use of two drugs, nifurtimox (Nfx) and benznidazole (Bnz), both of which present limited efficacy in the chronic stage of the disease and toxic side effects. Thus, the discovery of novel compounds is urgently required. Herein, we report the successful synthesis of 4-nitroimidazole analogs of Bnz via nucleophilic aromatic substitution or cycloaddition reactions. The analogs were biologically evaluated, and compound 4 (4-cyclopropyl-1-(1-methyl-4-nitro-1H-imidazole-5-yl)-1H-1,2,3-triazole) was identified as the most potent against both the trypomastigote (IC50 = 5.4 µM) and amastigote (IC50 = 12.0 µM) forms of T. cruzi, showing activity in the same range as Bnz (IC50 = 8.8 and 8.7 µM, respectively). The cytotoxic and genotoxic activities of compounds 5, 4 and 11 were assessed. These three compounds were cytotoxic and genotoxic to RAW and HepG2 cells and mutagenic to Salmonella enterica strains. However, 4 exhibited toxic effects only at concentrations higher than those needed for trypanocidal activity. Molecular docking of 4 showed the importance of the size and π-π interactions between the nitroimidazole and the cofactor (flavin mononucleotide) of T.cruzi-nitroreductase (TcNTR). Moreover, the residues His503 and Tyr545 are relevant for binding to TcNTR. Our design strategy was capable of generating novel and active Bnz analogs.


Assuntos
Antiprotozoários/farmacologia , Nitroimidazóis/farmacologia , Salmonella enterica/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Nitrorredutases/antagonistas & inibidores , Nitrorredutases/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia
12.
Curr Top Med Chem ; 20(2): 140-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31702503

RESUMO

INTRODUCTION: Structural modulation of previously identified lead spiro-ß-lactams with antimicrobial activity was carried out. OBJECTIVE: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. METHODS: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-ß-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. RESULTS: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied ß- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. CONCLUSION: The designed structural modulation of biologically active spiro-ß-lactams involved the replacement of the four-membered ß-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between ß- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the ß-lactamic core is a requirement for the activity against both HIV and Plasmodium.


Assuntos
Fármacos Anti-HIV/farmacologia , Antiprotozoários/farmacologia , HIV/efeitos dos fármacos , Lactamas/farmacologia , Plasmodium/efeitos dos fármacos , Compostos de Espiro/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Lactamas/síntese química , Lactamas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Testes de Sensibilidade Parasitária , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
13.
Med Chem ; 16(1): 39-51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31208311

RESUMO

BACKGROUND: Leishmaniasis is a neglected disease that does not have adequate treatment. It affects around 12 million people around the world and is classified as a neglected disease by the World Health Organization. In this context, strategies to obtain new, more active and less toxic drugs should be stimulated. Sources of natural products combined with synthetic and chemoinformatic methodologies are strategies used to obtain molecules that are most likely to be effective against a specific disease. Computer-Aided Drug Design has become an indispensable tool in the pharmaceutical industry and academia in recent years and has been employed during various stages of the drug design process. OBJECTIVES: Perform structure- and ligand-based approaches, synthesize and characterize some compounds with materials available in our laboratories to verify the method's efficiency. METHODS: We created a database with 33 cyclic imides and evaluated their potential anti- Leishmanial activity (L. amazonensis and L. donovani) through ligand- and structure-based virtual screening. A diverse set selected from ChEMBL databanks of 818 structures (L. donovani) and 722 structures (L. amazonensis), with tested anti-Leishmanial activity against promastigotes forms, were classified according to pIC50 values to generate and validate a Random Forest model that shows higher statistical indices values. The structures of four different L. donovani enzymes were downloaded from the Protein Data Bank and the imides' structures were submitted to molecular docking. So, with available materials and technical feasibility of our laboratories, we have synthesized and characterized seven compounds through cyclization reactions between isosafrole and maleic anhydride followed by treatment with different amines to obtain new cyclic imides to evaluate their anti-Leishmanial activity. RESULTS: In silico study allowed us to suggest that the cyclic imides 516, 25, 31, 24, 32, 2, 3, 22 can be tested as potential multitarget molecules for leishmanial treatment, presenting activity probability against four strategic enzymes (Topoisomerase I, N-myristoyltransferase, cyclophilin and Oacetylserine sulfhydrylase). The compounds synthesized and tested presented pIC50 values less than 4.7 for Leishmania amazonensis. CONCLUSION: After combined approach evaluation, we have synthesized and characterized seven cyclic imides by IR, 1H NMR, 13C-APT NMR, COSY, HETCOR and HMBC. The compounds tested against promastigote forms of L. amazonensis presented pIC50 values less than 4.7, showing that our method was efficient in predicting true negative molecules.


Assuntos
Antiprotozoários/farmacologia , Imidas/farmacologia , Leishmania/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Imidas/síntese química , Imidas/química , Ligantes , Estrutura Molecular , Testes de Sensibilidade Parasitária , Especificidade da Espécie , Relação Estrutura-Atividade
14.
Med Chem ; 16(1): 24-38, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31218962

RESUMO

More than 10 million people around the world are afflicted by Neglected Tropical Diseases, such as Chagas Disease, Human African Trypanosomiasis, and Leishmania. These diseases mostly occur in undeveloped countries that suffer from a lack of economic incentive, research, and policy for new compound development. Sulfonamide moieties are effective scaffolds present in several compounds that are determinants to treat various diseases, principally neglected tropical diseases. This review article examines the contribution of these scaffolds in medicinal chemistry in the last five years, focusing on three trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei, and Leishmania ssp. We also present perspectives for their use in drug designs in an effort to contribute to new drug development. In addition, we consider the physicochemical parameters, whose molecules all presented according to Lipinski's rule. The correlation between the selective index and LogP was evaluated, showing that sulfonamide derivatives can act differently against each trypanosomatid parasite. Moreover, the approaches of novel drugs and technologies are very important for the eventual drug discovery against trypanosomatid diseases.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Sulfonamidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Eur J Med Chem ; 186: 111860, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759728

RESUMO

Methionine aminopeptidase 1 of Leishmania donovani (LdMetAP1) is a novel antileishmanial target for its role in vital N-terminal methionine processing. After LdMetAP1 expression and purification, we employed a series of biochemical assays to determine optimal conditions for catalysis, metal dependence and substrate preferences for this ubiquitous enzyme. Screening of newly synthesized quinoline-carbaldehyde derivatives in inhibition assays led to the identification of HQ14 and HQ15 as novel and specific inhibitors for LdMetAP1 which compete with substrate for binding to the catalytic active site. Both leads bind LdMetAP1 with high affinity and possess druglikeness. Biochemical studies suggested HQ14 and HQ15 to be comparatively less effective against purified HsMetAP1 and showed no or less toxicity. We further show selectivity and inhibition of lead inhibitors is sensed through a non-catalytic Thr residue unique to LdMetAP1. Finally, structural studies highlight key differences in the binding modes of HQ14 and HQ15 to LdMetAP1 and HsMetAP1 providing structural basis for differences in inhibition. The study demonstrates the feasibility of deploying small drug like molecules to selectively target the catalytic activity of LdMetAP1 which may provide an effective treatment of leishmaniasis.


Assuntos
Aldeídos/farmacologia , Aminopeptidases/antagonistas & inibidores , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Quinolinas/farmacologia , Aldeídos/síntese química , Aldeídos/química , Aminopeptidases/metabolismo , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Leishmania donovani/enzimologia , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
16.
J Enzyme Inhib Med Chem ; 35(1): 199-210, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752556

RESUMO

Previous reports have validated the glycogen synthase kinase-3 (GSK-3) as a druggable target against the human protozoan parasite Leishmania. This prompted us to search for new leishmanicidal scaffolds as inhibitors of this enzyme from our in-house library of human GSK-3ß inhibitors, as well as from the Leishbox collection of leishmanicidal compounds developed by GlaxoSmithKline. As a result, new leishmanicidal inhibitors acting on Leishmania GSK-3 at micromolar concentrations were found. These inhibitors belong to six different chemical classes (thiadiazolidindione, halomethylketone, maleimide, benzoimidazole, N-phenylpyrimidine-2-amine and oxadiazole). In addition, the binding mode of the most active compounds into Leishmania GSK-3 was approached using computational tools. On the whole, we have uncovered new chemical scaffolds with an appealing prospective in the development and use of Leishmania GSK-3 inhibitors against this infectious protozoan.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Leishmania/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Leishmania/citologia , Leishmania/enzimologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
17.
J Enzyme Inhib Med Chem ; 35(1): 377-382, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31856608

RESUMO

The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum, have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (KIs 0.81-65.4 µM) and PfCA (KIs 0.62-78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA, which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria.


Assuntos
Antiprotozoários/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Diatomáceas/enzimologia , Fenóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Fenóis/síntese química , Fenóis/química , Plasmodium falciparum/enzimologia , Relação Estrutura-Atividade
18.
Parasitol Int ; 74: 101961, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31437553

RESUMO

Natural resources are recognized as important sources of potential drugs for treating various infections, and microorganisms are a rich natural source of diverse compounds. Among the world's microorganisms, actinomycetes, which are abundant in soil and marine, are the well-known producers of a wide range of bioactive secondary metabolites and antibiotics. In the present study, four actinomycetes (samples N25, N6, N18, and N12) were isolated from soil samples in Mongolia. Phylogenetic analysis of these isolates revealed that they share the highest similarity with Streptomyces canus (N25), S. cirratus (N6), S. bacillaris (N18) and S. peucetius (N12), based on 16S rRNA gene sequencing. Crude extracts were obtained from them using ethyl acetate, and the crude fractions were separated by thin layer chromatography. The fractions were then evaluated for their cytotoxicities and their anti-Toxoplasma and antimalarial activities in vitro. The S. canus (N25) crude extract was selected for further chemical characterization based on its antiprotozoal activities. Using liquid chromatography-high resolution mass spectrometry, phenazine-1-carboxylic acid (PCA) was detected and identified in the active fractions of the metabolites from strain N25. We next confirmed that commercially available PCA possesses antiprotozoal activity against T. gondii (IC50: 55.5 µg/ml) and Plasmodium falciparum (IC50: 6.4 µg/ml) in vitro. The results of this study reveal that soil actinomycetes are potential sources of antiprotozoal compounds, and that PCA merits further investigation as an anti-protozoal agent.


Assuntos
Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Microbiologia do Solo , Streptomyces/química , Streptomyces/classificação , Mongólia , Filogenia , RNA Ribossômico 16S/genética , Streptomyces/isolamento & purificação
19.
Molecules ; 24(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795283

RESUMO

Parasitic infections like leishmaniasis and trypanosomiasis remain as a worldwide concern to public health. Improvement of the currently available drug discovery pipelines for those diseases is therefore mandatory. We have recently reported on the antileishmanial and antitrypanosomal activity of a set of cinnamate esters where we identified several compounds with interesting activity against L. donovani and T. brucei rhodesiense. For a better understanding of such compounds' anti-infective activity, analyses of the underlying structure-activity relationships, especially from a quantitative point of view, would be a prerequisite for rational further development of such compounds. Thus, quantitative structure-activity relationships (QSAR) modeling for the mentioned set of compounds and their antileishmanial and antitrypanosomal activity was performed using a genetic algorithm as main variable selection tool and multiple linear regression as statistical analysis. Changes in the composition of the training/test sets were evaluated (two randomly selected and one by Kennard-Stone algorithm). The effect of the size of the models (number of descriptors) was also investigated. The quality of all resulting models was assessed by a variety of validation parameters. The models were ranked by newly introduced scoring functions accounting for the fulfillment of each of the validation criteria evaluated. The test sets were effectively within the applicability domain of the best models, which demonstrated high robustness. Detailed analysis of the molecular descriptors involved in those models revealed strong dependence of activity on the number and type of polar atoms, which affect the hydrophobic/hydrophilic properties causing a prominent influence on the investigated biological activities.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Relação Quantitativa Estrutura-Atividade , Ésteres , Leishmania/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Reprodutibilidade dos Testes , Trypanosoma/efeitos dos fármacos
20.
Molecules ; 24(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31817023

RESUMO

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of parasitic protozoa. The essential oil was obtained by hydrodistillation from the dried herbal parts of O. onites and analyzed by Gas Chromatography-Flame Ionization Detector (GC-FID) and Gas Chromatography coupled with Mass Spectrometry (GC-MS). The in vitro activity of the oil and its major components were evaluated against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. The main component of the oil was identified as carvacrol (70.6%), followed by linalool (9.7%), p-cymene (7%), γ-terpinene (2.1%), and thymol (1.8%). The oil showed significant in vitro activity against T. b. rhodesiense (IC50 180 ng/mL), and moderate antileishmanial and antiplasmodial effects, without toxicity to mammalian cells. Carvacrol, thymol, and 10 additional abundant oil constituents were tested against the same panel; carvacrol and thymol retained the oil's in vitro antiparasitic potency. In the T. b. brucei mouse model, thymol, but not carvacrol, extended the mean survival of animals. This study indicates the potential of the essential oil of O. onites and its constituents in the treatment of protozoal infections.


Assuntos
Antiprotozoários/administração & dosagem , Antiprotozoários/química , Óleos Voláteis/administração & dosagem , Óleos Voláteis/química , Origanum/química , Tripanossomíase Africana/tratamento farmacológico , Animais , Antiprotozoários/farmacologia , Cimenos/administração & dosagem , Cimenos/farmacologia , Modelos Animais de Doenças , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Óleos Voláteis/farmacologia , Óleos Vegetais/química , Óleos Vegetais/farmacologia , Timol/administração & dosagem , Timol/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos
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