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1.
Parasitol Res ; 119(10): 3503-3515, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772176

RESUMO

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.


Assuntos
Amino Álcoois/farmacologia , Antiprotozoários/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Babesia/efeitos dos fármacos , Babesia/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Modelos Animais de Doenças , Leishmania/efeitos dos fármacos , Leishmania/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Plasmodium/efeitos dos fármacos , Plasmodium/crescimento & desenvolvimento , Infecções por Protozoários/tratamento farmacológico , Infecções por Protozoários/parasitologia , Resultado do Tratamento , Trypanosoma/efeitos dos fármacos , Trypanosoma/crescimento & desenvolvimento , Células Vero
2.
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
3.
J Enzyme Inhib Med Chem ; 35(1): 639-649, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32048531

RESUMO

Leishmaniasis is a neglected disease caused by the protozoa Leishmania ssp. Environmental differences found by the parasites in the vector and the host are translated into cellular stress, leading to the production of heat shock proteins (Hsp). These are molecular chaperones involved in the folding of nascent proteins as well as in the regulation of gene expression, signalling events and proteostasis. Since Leishmania spp. use Hsp90 to trigger important transitions between their different stages of the life cycle, this protein family becomes a profitable target in anti-parasite drug discovery. In this work, we implemented a multidisciplinary strategy coupling molecular modelling with in vitro assays to identify small molecules able to inhibit Hsp90 from L. braziliensis (LbHsp90). Overall, we identified some compounds able to kill the promastigote form of the L. braziliensis, and to inhibit LbHsp90 ATPase activity.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Leishmania braziliensis/efeitos dos fármacos , Chaperonas Moleculares/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteínas de Choque Térmico HSP90/metabolismo , Leishmania braziliensis/química , Modelos Moleculares , Chaperonas Moleculares/síntese química , Chaperonas Moleculares/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 191: 112146, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088496

RESUMO

In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how functionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and antitrypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC50 > 10 µM (vs 0.18 µM and 2.31 µM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 µM ≤ IC50 ≤ 2.18 µM vs IC50 = 2.31 µM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC50 > 10 µM).


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Nitroimidazóis/farmacologia , Oxazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Oxazóis/síntese química , Oxazóis/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
5.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059495

RESUMO

We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1-5) and secnidazole (6-10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 1-10 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 µM. Molecular dynamics of compounds 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate-ferredoxin oxidoreductase of T. vaginalis and the modeled -tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs.


Assuntos
Antiprotozoários/farmacologia , Carbamatos/química , Metronidazol/análogos & derivados , Metronidazol/química , Antiprotozoários/síntese química , Antiprotozoários/química , Carbamatos/síntese química , Carbamatos/farmacologia , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/patogenicidade , Giardíase/tratamento farmacológico , Giardíase/parasitologia , Metronidazol/síntese química , Metronidazol/farmacologia , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/patogenicidade
6.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059518

RESUMO

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC50 values lower than 40 µM, but only four compounds displayed the highest antileishmanial activity, with EC50 values below 10 µM; these all compounds possess a good Selectivity Index > 2.6. Although two active compounds were thiochromenes, a clear structure-activity relationship was not detected since each active compound has a different substitution pattern.


Assuntos
Antiprotozoários/farmacologia , Proliferação de Células/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Piranos/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Humanos , Leishmania/patogenicidade , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piranos/síntese química , Piranos/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química
7.
Molecules ; 25(2)2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31940910

RESUMO

Interest in the synthesis of Bi(III) and Sb(III) dithiocarbamate complexes is on the rise, and this has been attributed to their wide structural diversity and their interesting application as biological agents and in solid state/materials chemistry. The readily available binding sites of the two sulphur atoms within the dithiocarbamate moiety in the complexes confers a wide variety of geometry and interactions that often leads to supramolecular assemblies. Although none of the bismuth or antimony metals are known to play any natural biological function, their dithiocarbamate complexes, however, have proven very useful as antibacterial, antileishmanial, anticancer, and antifungal agents. The dithiocarbamate ligands modulate the associated toxicity of the metals, especially antimony, since bismuth is known to be benign, allowing the metal ion to get to the targeted sites; hence, making it less available for side and other damaging reactions. This review presents a concise chemistry and some known biological potentials of their trivalent dithiocarbamate complexes.


Assuntos
Antimônio/química , Bismuto/química , Complexos de Coordenação/síntese química , Tiocarbamatos/síntese química , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antimônio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Bismuto/farmacologia , Complexos de Coordenação/farmacologia , Humanos , Modelos Químicos , Tiocarbamatos/farmacologia
8.
Org Biomol Chem ; 18(4): 767-770, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31912847

RESUMO

Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is the synthesis of miltefosine, the lone oral drug approved to treat leishmaniasis. Due to its prohibitive expense ($1500 per g), miltefosine is not accesable for the majority of the world's patients. Based on the described reaction sequence, this drug can be produced for $25 per g.


Assuntos
Álcoois/química , Indicadores e Reagentes/química , Fosforilcolina/análogos & derivados , Antiprotozoários/síntese química , Indicadores e Reagentes/síntese química , Modelos Químicos , Oxirredução , Fosforilcolina/síntese química
9.
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
10.
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
11.
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
12.
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
13.
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
14.
Arch Pharm (Weinheim) ; 353(2): e1900241, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31840866

RESUMO

Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45-91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p-r were active on both the promastigote and amastigote forms, with emphasis on compound 14p, which showed strong activity against the amastigote form (IC50 = 0.6 µM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC50 = 8.5 µM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC50 = 1.2 µM and SI = 20.2); compound 14h, with IC50 = 7.0 µM and SI = 6.1; and compound 14j containing the 4-SCH3 group, with IC50 = 5.7 µM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 µM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 µM for C. glabrata, lower than that of the fluconazole used as the reference drug.


Assuntos
Antifúngicos/farmacologia , Antiprotozoários/farmacologia , Candida/efeitos dos fármacos , Desenho de Fármacos , Isoxazóis/farmacologia , Leishmania/efeitos dos fármacos , Nitrofuranos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Isoxazóis/síntese química , Isoxazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nitrofuranos/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
15.
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
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.
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
18.
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
19.
SAR QSAR Environ Res ; 30(12): 919-933, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702401

RESUMO

Folates are essential biomolecules required to carry out many crucial processes in leishmania parasite. Dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) involved in folate biosynthesis in leishmania have been established as suitable targets for development of chemotherapy against leishmaniasis. In the present study, various computational tools such as homology modelling, pharmacophore modelling, docking, molecular dynamics and molecular mechanics have been employed to design dual DHFR-TS and PTR1 inhibitors. Two designed molecules, i.e. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were synthesized. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to evaluate in vitro activity of molecules against promastigote form of Leishmania donovani using Miltefosine as standard. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were found to be moderately active with showed IC50 = 68 ± 2.8 µM and 57 ± 4.2 µM, respectively.


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Complexos Multienzimáticos/química , Oxirredutases/química , Proteínas de Protozoários/química , Tetra-Hidrofolato Desidrogenase/química , Timidilato Sintase/química , Antiprotozoários/síntese química , Antiprotozoários/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Descoberta de Drogas , Concentração Inibidora 50 , Leishmania donovani/metabolismo , Modelos Moleculares , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Relação Estrutura-Atividade
20.
J Med Chem ; 62(23): 10664-10675, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31702921

RESUMO

We report the discovery of new 4-hydroxyphenyl phosphonium salt derivatives active in the submicromolar range (EC50 from 0.04 to 0.28 µM, SI > 10) against the protozoan parasite Leishmania donovani. The pharmacokinetics and in vivo oral efficacy of compound 1 [(16-(2,4-dihydroxyphenyl)-16-oxohexadecyl)triphenylphosphonium bromide] in a mouse model of visceral leishmaniasis were established. Compound 1 reduced the parasite load in spleen (98.9%) and liver (95.3%) of infected mice after an oral dosage of four daily doses of 1.5 mg/kg. Mode of action studies showed that compound 1 diffuses across the plasma membrane, as designed, and targets the mitochondrion of Leishmania parasites. Disruption of the energetic metabolism, with a decrease of intracellular ATP levels as well as mitochondrial depolarization together with a significant reactive oxygen species production, contributes to the leishmanicidal effect of 1. Importantly, this compound was equally effective against antimonials and miltefosine-resistant clinical isolates of Leishmania infantum, indicating its potential as antileishmanial lead.


Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Animais , Antiprotozoários/síntese química , Fragmentação do DNA , Descoberta de Drogas , Resistência a Medicamentos , Feminino , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Espécies Reativas de Oxigênio , Relação Estrutura-Atividade
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