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1.
Phytother Res ; 35(3): 1399-1415, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33034100

RESUMO

The anxiolytic activity of Psidium guajava L. leaf ethanolic extract (PLE) and its effect on neurotransmitter systems was investigated. PLE, extracted using Soxhlet apparatus, was subjected to preliminary qualitative and quantitative (flavonoids and phenols) analyses. The anxiolytic activity at 100, 200, and 400 mg/Kg doses were assessed in mice using elevated plus maze (EPM) and light/dark transition (LDT) test models on days 1 and 16. Neurotransmitters such as monoamines (serotonin, norepinephrine, and dopamine), γ-aminobutyric acid (GABA), and glutamate were estimated in different regions of the brain (cortex, hippocampus, and cerebellum and brain stem). Phytoconstituents identified using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry were analyzed in silico to evaluate their potential binding mode(s) to GABAA and 5-HT1A receptors. Phytochemical studies showed the presence of alkaloids, tannins, flavonoids, saponins, anthraquinone glycosides, carbohydrates, and proteins, whereas total flavonoid and phenol contents were estimated to be 64.96 ± 0.95 and 206.58 ± 1.60 mg/g of dried extract, respectively. PLE treatment significantly enhanced exploratory activity of mice in EPM and LDT models with significant effects on monoamines, GABA and glutamate levels in the brain. The in silico studies suggested the interaction(s) of PLE component(s) with GABAA /5-HT1A receptors as a potential mechanism of its anxiolytic activity.


Assuntos
Ansiolíticos/uso terapêutico , Neurotransmissores/metabolismo , Extratos Vegetais/química , Psidium/química , Animais , Ansiolíticos/farmacologia , Masculino , Camundongos
2.
RSC Adv ; 9(69): 40228-40239, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-35542690

RESUMO

The emergence of multidrug-resistant (MDR) bacterial strains in the last decade is astonishingly alarming. Many of the widely used antibiotics have failed to exhibit clinical efficacy against such strains. Eventually we will exhaust all the resources in our antibiotic armamentarium. As a need of the hour, novel strategies are desperately required not only to curb, but also to reverse, the development of resistance in these pathogens, thereby maintaining their sensitivity towards current antibiotics. Intervention of bacterial virulence, rather than killing them, by inhibiting specific pathways/targets has emerged as a novel approach to tackle the drug resistance problem. The bacterial virulence is regulated via quorum-sensing, a cell-cell communication process precisely controlled by autoinducer molecules such as acyl homoserine lactone (AHL). The present study aimed at identifying promising quorum-sensing inhibitors in Pseudomonas aeruginosa, an opportunistic human pathogen especially associated with nosocomial infections, yielding four potential hits. Out of these, potassium 2-methoxy-4-vinylphenolate was the most potent quorum-sensing inhibitor targeting P. aeruginosa LasIR/RhlIR circuitry. It also inhibited biofilm formation, various virulence factors like LasA protease, LasB elastase and pyocyanin, and motility of bacteria like swarming and twitching.

4.
Drug Dev Res ; 80(1): 125-132, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30381846

RESUMO

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3-triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9-99.9% and 16-57%, respectively, at 10 µM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 µM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , IMP Desidrogenase/antagonistas & inibidores , Antibacterianos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/síntese química , Humanos , IMP Desidrogenase/metabolismo , Simulação de Acoplamento Molecular/métodos , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 164: 193-213, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30594677

RESUMO

During cancer chemotherapy, certain cancers may become cross-resistant to structurally diverse antineoplastic agents. This so-called multidrug resistance (MDR) is highly associated with the overexpression of ATP-binding cassette (ABC) transport proteins. These membrane-bound efflux pumps export a broad range of structurally diverse endo- and xenobiotics, including chemically unrelated anticancer agents. This translocation of drugs from the inside to the outside of cancer cells is mediated at the expense of ATP. In the last 40 years, three ABC transporters - ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) - have mainly been attributed to the occurrence of MDR in cancer cells. One of the strategies to overcome MDR is to inhibit the efflux transporter function by small-molecule inhibitors. In this work, we investigated new chalcone- and flavone-based compounds for selective as well as broad-spectrum inhibition of the stated transport proteins. These include substituted chalcones with variations at rings A and B, and flavones with acetamido linker at position 3. The synthesized molecules were evaluated for their inhibitory potential against ABCB1, ABCC1, and ABCG2 in calcein AM and pheophorbide A assays. In further investigations with the most promising candidates from each class, we proved that ABCB1- and ABCG2-mediated MDR could be reversed by the compounds. Moreover, their intrinsic toxicity was found to be negligible in most cases. Altogether, our findings contribute to the understanding of ABC transport proteins and reveal new compounds for ongoing evaluation in the field of ABC transporter-mediated MDR.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/síntese química , Chalconas/farmacologia , Flavonas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Chalconas/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Flavonas/uso terapêutico , Humanos , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 28(10): 1714-1718, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29699922

RESUMO

Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.


Assuntos
Antituberculosos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , IMP Desidrogenase/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade
7.
Life Sci ; 185: 73-84, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28720470

RESUMO

AIM: The study is aimed at evaluating the chemosensitization and apoptotic effect of aglycone rich extracts of dietary phytoestrogens (derived from soybean and flaxseed) on estrogen receptor positive, MCF-7 and estrogen receptor negative, MDA-MB-231 cells. The extracts show potent activity on both the cell lines, hence, in silico studies have been carried out to find the possible reason for their activity. MAIN METHODS: MTT assay was carried to assess chemosensitization effect and activated caspase-3/7 activity was studied using flow-cytometry and western blotting. In silico studies were carried out using PharmMapper and the top hits were taken up for docking using the Schrödinger software. Top molecular targets were subjected to gene expression studies by qPCR and protein expression using Western blot analysis. KEY FINDINGS: This study reports the apoptotic activity and chemosensitization effect of the phytoestrogens. Molecular docking studies predict AKR1B1 (aldose reductase), HRAS (Harvey rat sarcoma) and GSTP1 (glutathione s-transferase pi) as potential molecular targets for genistein, daidzein and secoisolariciresinol, respectively. Gene and protein expression studies show down-regulation of AKR1BI, HRAS and GSTP1 by the extracts. SIGNIFICANCE: The qPCR and western blot analysis results support the computational analyses, and hence genistein, daidzein and secoisolariciresinol may be considered as good candidates for future development into potent inhibitors of the respective protein targets through medicinal chemistry optimization.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Simulação de Acoplamento Molecular , Fitoestrógenos/farmacologia , Western Blotting , Neoplasias da Mama/patologia , Butileno Glicóis/farmacologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Simulação por Computador , Regulação para Baixo/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genisteína/farmacologia , Humanos , Isoflavonas/farmacologia , Lignanas/farmacologia , Células MCF-7
8.
Curr Top Med Chem ; 16(19): 2069-77, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26881717

RESUMO

Computational drug repositioning is popular in academia and pharmaceutical industry globally. The repositioning hypotheses, generated using a variety of computational methods, can be quickly tested experimentally. Several success stories have emerged in the past decade or so. Newer concepts and methods such as drug profile matching are being tried to address the limitations of current computational repositioning methods. The trend is shifting from earlier small-scale to large-scale or global-scale repositioning applications. Other related approaches such as prediction of molecular targets for novel molecules, prediction of side-effect profiles of new molecular entities (NMEs), etc., are applied routinely. The current article focuses on state-of-the-art of computational drug repositioning field with the help of relevant examples and case studies. This 'lateral' approach has significant potential to bring down the time and cost of the awfully expensive drug discovery research and clinical development. The persistence and perseverance in the successful application of these methods is likely to be paid off in near future.


Assuntos
Biologia Computacional/métodos , Reposicionamento de Medicamentos/métodos , Algoritmos , Bases de Dados Factuais , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Ligantes , Aprendizado de Máquina , Biologia de Sistemas/métodos , Interface Usuário-Computador
9.
Chem Biol Drug Des ; 84(5): 593-602, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24797717

RESUMO

Herein, we report synthesis and screening of a series of twenty derivatives of bromopyrrole alkaloids with aroyl hydrazone feature for antidepressant activity by forced swim test (FST), tail suspension test (TST), and actophotometer method. The molecules were further evaluated for in vitro human MAO's inhibitory activities. The tested compounds exhibited moderate to good antidepressant activity compared with standard fluoxetine. Among these, most promising antidepressant derivatives 5b (%DID = 60.48), 5e (%DID = 59), and 5j (%DID = 74.86) reduced immobility duration of 50-70% at 30 mg/kg dose levels in FST. Further, derivative 5b, 5e, and 5j displayed good antidepressant activity with %DID value of 47.50, 46.62, and 52.49, respectively, in TST compared with standard fluoxetine (66.56% DID). Compound 5b showed high in vitro MAO-A potency and selectivity (Ki MAO-A (µM) = 2.4 ± 0.99, SI = 0.06) with promising pharmacological activity recognizing its potential as antidepressant lead candidate for further drug development. Study revealed that the presence of halogen atoms such as chlorine and fluorine at ortho- and/or para-position of phenyl ring and N-alkylation of pyrrole core is favored features for antidepressant activity.


Assuntos
Antidepressivos/química , Antidepressivos/farmacologia , Alcaloides/química , Animais , Antidepressivos/síntese química , Organismos Aquáticos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Elevação dos Membros Posteriores , Humanos , Camundongos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Pirróis/química , Testes de Toxicidade Aguda
10.
J Enzyme Inhib Med Chem ; 29(3): 401-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23663080

RESUMO

A novel set of 16 hybrids of bromopyrrole alkaloids with aroyl hydrazone were designed, synthesized and evaluated for antibacterial and antibiofilm activities against methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43866), methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 35556) and Staphylococcus epidermidis (SE, S. epidermidis ATCC 35984). Of the 16 tested hybrids, 14 exhibited equal or superior antibiofilm activity against MSSA and MRSA relative to standard vancomycin. Compound 4m showed highest potency with antibiofilm activity of 0.39 µg/mL and 0.78 µg/mL against MSSA and MRSA, respectively. Thus, this compound could act as a potential lead for further development of new antistaphylococcal drugs.


Assuntos
Alcaloides/síntese química , Antibacterianos/síntese química , Biofilmes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pirróis/síntese química , Staphylococcus epidermidis/efeitos dos fármacos , Alcaloides/química , Alcaloides/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Desenho de Fármacos , Farmacorresistência Bacteriana , Hidrazonas/química , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Poríferos/química , Pirróis/química , Pirróis/farmacologia , Staphylococcus epidermidis/crescimento & desenvolvimento , Tiazolidinas/química , Vancomicina/farmacologia
11.
Eur J Med Chem ; 63: 793-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23584542

RESUMO

A series of twenty three novel hybrids of marine bromopyrrole alkaloids with chalcone, isoxazole and flavone structural features were synthesized and evaluated for in vitro anticancer activity by MTT assay against five human cancer cell lines. Among the synthesized chalcones, hybrids 4a and 4h (IC50 range: 0.18 µM-12.00 µM) showed anticancer activity against all the tested cancer cell lines. Promising cytotoxic activities were exhibited by flavones derivatives, 5a and 5b (0.41 µM-1.28 µM) against cell lines PA1 and KB403. Isoxazole hybrids, 6b-6e selectively inhibited oral and mouth cancer cell line KB403, among which 6c (IC50 = 2.45 µM) was found to be most active.


Assuntos
Alcaloides/química , Antineoplásicos/química , Antineoplásicos/síntese química , Pirróis/química , Animais , Antineoplásicos/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Chalcona/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flavonas/síntese química , Flavonas/química , Flavonas/farmacologia , Humanos , Concentração Inibidora 50 , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Células MCF-7 , Biologia Marinha , Modelos Químicos , Estrutura Molecular
12.
Bioorg Med Chem Lett ; 22(23): 7131-4, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23084904

RESUMO

4-Thiazolidinones derivatives of marine bromopyrrole alkaloids were synthesized as potential antibiofilm compounds. Among the synthesized compounds, some showed promising antibiofilm activity. Biological data revealed that 1,3-thiazolidin-4-one derivatives are more potent antibiofilm agents compared to 1,3-thiazinan-4-ones. Antibiofilm activity of compound 4b, 4c (MIC=0.78 µg/ml) was 3-fold superior than standard vancomycin (MIC=3.125 µg/ml) while activity of compound 4d, 4f, 4g and 4h was 2-fold (MIC=1.56 µg/ml) against Staphylococcus aureus biofilm. Compound 4b-4h showed equal antibiofilm activity against Staphylococcus epidermidis compared to standard Vancomycin (MIC=3.125 µg/ml).


Assuntos
Antibacterianos/síntese química , Biofilmes/efeitos dos fármacos , Tiazolidinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Alcaloides/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Pirróis/química , Staphylococcus aureus/fisiologia , Staphylococcus epidermidis/fisiologia , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química , Vancomicina/farmacologia
13.
Bioorg Med Chem Lett ; 22(20): 6429-32, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22967765

RESUMO

In an attempt to identify new potential lead as antimicrobial agent, twenty hybrids of marine bromopyrrole alkaloids with 1,3,4-oxadiazole were designed based on molecular hybridization technique and synthesized. Synthesized molecules were evaluated for their antibacterial, antifungal and antitubercular activities. Hybrids 5d, 5i, 5j and 5k exhibited equivalent antibacterial activity (MIC of 1.56 µg/mL) compared with standard drug ciprofloxacin against Staphylococcus aureus and Escherichia coli. Equal antifungal activity (MIC of 1.56 µg/mL) was shown by of hybrids 5j, 5k and 7d compared with standard Amphotericin-B. The inhibition of Mycobacterium tuberculosis at concentrations as low as 1.6 and 1.5 µg/mL by compounds 5f and 7d respectively indicates that these compounds can act as leads for development of newer anti-TB compounds.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Alcaloides/síntese química , Anti-Infecciosos/síntese química , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Fungos/efeitos dos fármacos , Halogenação , Humanos , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Oxidiazóis/síntese química , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia
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