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1.
Int J Mol Sci ; 25(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38397115

RESUMO

Zika virus (ZIKV) is a positive-sense single-stranded virus member of the Flaviviridae family. Among other arboviruses, ZIKV can cause neurological disorders such as Guillain Barré syndrome, and it can have congenital neurological manifestations and affect fertility. ZIKV nonstructural protein 5 (NS5) is essential for viral replication and limiting host immune detection. Herein, we performed virtual screening to identify novel small-molecule inhibitors of the ZIKV NS5 methyltransferase (MTase) domain. Compounds were tested against the MTases of both ZIKV and DENV, demonstrating good inhibitory activities against ZIKV MTase. Extensive molecular dynamic studies conducted on the series led us to identify other derivatives with improved activity against the MTase and limiting ZIKV infection with an increased selectivity index. Preliminary pharmacokinetic parameters have been determined, revealing excellent stability over time. Preliminary in vivo toxicity studies demonstrated that the hit compound 17 is well tolerated after acute administration. Our results provide the basis for further optimization studies on novel non-nucleoside MTase inhibitors.


Assuntos
Infecção por Zika virus , Zika virus , Humanos , Zika virus/metabolismo , Infecção por Zika virus/tratamento farmacológico , Modelos Moleculares , Antivirais/química , Proteínas não Estruturais Virais/metabolismo
2.
Bioorg Med Chem Lett ; 27(15): 3332-3336, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28610983

RESUMO

In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.


Assuntos
Antifúngicos/farmacologia , Quitinases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Trichoderma/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Quitinases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Trichoderma/enzimologia
3.
ACS Med Chem Lett ; 14(4): 417-424, 2023 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-37077400

RESUMO

Our research group has been involved for a long time in the development of macrocyclic amidinoureas (MCAs) as antifungal agents. The mechanistic investigation drove us to perform an in silico target fishing study, which allowed the identification of chitinases as one of their putative targets, with 1a showing a submicromolar inhibition of Trichoderma viride chitinase. In this work, we investigated the possibility to further inhibit the corresponding human enzymes, acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1), involved in several chronic inflammatory lung diseases. Thus, we first validated the inhibitory activity of 1a against AMCase and CHIT1 and then designed and synthesized new derivatives aimed at improving the potency and selectivity against AMCase. Among them, compound 3f emerged for its activity profile along with its promising in vitro ADME properties. We also gained a good understanding of the key interactions with the target enzyme through in silico studies.

4.
J Biomol Struct Dyn ; 39(16): 6242-6248, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32705942

RESUMO

Accepted 7 July 2020ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the known COVID-19 disease. Since currently no definitive therapies or vaccines for the SARS-CoV-2 virus are available, there is an urgent need to identify effective drugs against SARS-CoV-2 infection. One of the best-known targets available is the main protease of this virus, crucial for the processing of polyproteins codified by viral RNA. In this work, we used a computational virtual screening procedure for the repurposing of commercial drugs available in the DrugBank database as inhibitors of the SARS-CoV-2 main protease. Molecular docking calculations and molecular dynamics (MD) simulations have been applied. The computational model was validated through a self-docking procedure. The screening procedure highlighted five interesting drugs that showed a comparable or higher docking score compared to the crystallographic compound and maintained the protein binding during the MD runs. Amongst these drugs, Ritonavir has been used in clinical trials with patients affected by COVID-19 and Nelfinavir showed anti-SARS-CoV-2 activity. The five identified drugs could be evaluated experimentally as inhibitors of the SARS-CoV-2 main protease in view of a possible COVID-19 treatment. Communicated by Ramaswamy H. Sarma.


Assuntos
Tratamento Farmacológico da COVID-19 , Inibidores de Proteases , Vacinas contra COVID-19 , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2
5.
ACS Med Chem Lett ; 11(5): 1035-1040, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32435422

RESUMO

Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity in vitro. These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. In silico molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.

6.
Int J Antimicrob Agents ; 55(3): 105865, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31866465

RESUMO

BACKGROUND: Candida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains. OBJECTIVE: A compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety. METHODS: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution. RESULTS: The current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains. CONCLUSIONS: The results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Guanidina/análogos & derivados , Ureia/análogos & derivados , Animais , Antifúngicos/uso terapêutico , Azóis/farmacologia , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica/efeitos dos fármacos , Guanidina/farmacologia , Guanidina/uso terapêutico , Testes de Sensibilidade Microbiana , Ratos , Ureia/farmacologia , Ureia/uso terapêutico
7.
Eur J Med Chem ; 121: 169-180, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27240272

RESUMO

The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 µg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Simulação por Computador , Descoberta de Drogas , Ligantes , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
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