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1.
Mol Divers ; 25(1): 191-204, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32086698

RESUMO

A library of pyrazole-thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier-Haack reaction. The compounds were tested for anti-microbial activity against two Gram-positive bacteria (Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) and four Gram-negative bacteria (Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa). Among the compounds tested, 3-((2,4-dichlorophenyl)-1-(2,4-dinitrophenyl)-1H-pyrazol-yl)methylene)hydrazinecarbothioamide (3a) and 2-((3-(2-chlorophenyl)-1-(2,4 dinitrophenyl)-1H-pyrazol-4-yl)methyleneamino)thiazolidin-4-one (4b) emerged as the most potent anti-microbial compounds with minimum bactericidal concentrations of < 0.2 µM against MRSA and S. aureus. Structure-activity relationship analysis further revealed that the presence of 2,4-dichloro moiety surprisingly influenced the activity of the compounds. Molecular docking studies of the compounds into the crystal structure of topoisomerase II and topoisomerase IV suggest that compounds 3a and 4b preferably interact with the targets through hydrogen bonding.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hidrazinas/química , Testes de Sensibilidade Microbiana/métodos , Simulação de Acoplamento Molecular/métodos , Relação Estrutura-Atividade , Tioamidas/química
2.
Eur J Med Chem ; 161: 456-467, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384048

RESUMO

Despite new agent development and short-term benefits in patients with colorectal cancer (CRC), metastatic CRC cure rates have not improved due to high rates of 5-fluorouracil (5-FU)/leucovorin/oxaliplatin (FOLFOX)-resistance and a clinical therapeutic plateau. At the same time, this treatment regime leads to significant toxicity, cost, and patient inconvenience. Drug-resistance is linked to CRC stem cells, which are associated with the epidermal-to-mesenchymal transition (EMT) pathway. Thus, to optimally treat CRC, a therapy that can target the cell survival and EMT pathways in both CRC bulk and stem cell populations is critical. We recently identified a novel small molecule NSC30049 (7a) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC bulk, FOLFOX-resistant, and CRC stem cells both in vitro and in vivo models. In the present study, we report the synthesis and anti-CRC evaluation of several stable and effective 7a analogs. ASR352 (7b) was identified as one of the equipotent 7a analogs that inhibited the growth of CRC bulk cells, sensitized FOLFOX-resistant cells, and reduced the sphere formation capacity of CRC stem cells. It appears that the complex mechanism of cytotoxicity for 7b includes abrogation of 5-FU-induced the S phase, reduction of the phosphorylation of Chk1 at S317P, S345P and S296P, increased γH2AX staining, activation of caspase 3/PARP1 cleavage, and enhancement of Bax/Bcl2 ratio. Further 7b-mediated reduced phosphorylation of Chk1 was an indirect effect, since it did not inhibit Chk1 activity in an in vitro kinase assay. Our findings suggest that 7b as a single agent, or in combination with 5-FU can be developed as a therapeutic agent in CRC bulk, FOLFOX-resistant, and CRC stem cell populations for unmanageable metastatic CRC conditions.


Assuntos
Adamantano/análogos & derivados , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Oxaliplatina/farmacologia , Células-Tronco/efeitos dos fármacos , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/química , Células HCT116 , Células HT29 , Humanos , Estrutura Molecular , Oxaliplatina/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
ACS Omega ; 3(9): 12106-12113, 2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30320289

RESUMO

1H-1,2,3-Triazole tethered imidazole-isatin and imidazole-isatin-thiosemicarbazone conjugates were synthesized and evaluated against MCF-7 and MDA-MB-231 cell lines. Antiproliferative activities of the synthesized conjugates revealed an optimum combination of longer alkyl chain length as spacer and a halogen-substituent on the isatin ring as a pre-requisite for good activity. The compound 6g with an optimum combination of chloro-substituent at C-5 position of isatin ring and a butyl chain length proved to be most active and noncytotoxic with IC50s of 54.25 and 26.12 µM against MCF-7 and MDA-MB-231 cell lines, respectively.

4.
Bioorg Med Chem ; 26(21): 5612-5623, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30360952

RESUMO

A novel library of coumarin tagged 1,3,4 oxadiazole conjugates was synthesized and evaluated for their antiproliferative activities against MDA-MB-231 and MCF-7 breast cancer cell lines. The evaluation studies revealed that compound 9d was the most potent molecule with an IC50 value of <5 µM against the MCF-7 cell line. Interestingly, compounds 10b and 11a showed a similar trend with lower inhibitory concentration (IC50 = 7.07 µM), in Estrogen Negative (ER-) cells than Estrogen Positive (ER+) cells. Structure-activity relationship (SAR) studies revealed that conjugates bearing benzyl moieties (9b, 9c and 9d) had superior activities compared to their alkyl analogues. The most potent compound 9d showed ∼1.4 times more potent activity than tamoxifen against MCF-7 cell line; while the introduction of sulfone unit in compounds 11a, 11b and 11c resulted in significant cytotoxicity against both MCF-7 and MDA-MB-231 cell lines. These results were further supported by docking studies, which revealed that the stronger binding affinity of the synthesized conjugates is due to the presence of sulfone unit attached to the substituted benzyl moiety in their pharmacophores.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Oxidiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/química , Receptores ErbB/química , Receptor alfa de Estrogênio/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 152: 436-488, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29751237

RESUMO

Diabetes mellitus is a medical condition characterized by the body's loss of control over blood sugar. The frequency of diagnosed cases and consequential increases in medical costs makes it a rapidly growing chronic disease that threatens human health worldwide. In addition, its unnerving statistical projections are perilous to both the economy of the nation and man's life expectancy. Type-I and type-II diabetes are the two clinical forms of diabetes mellitus. Type-II diabetes mellitus (T2DM) is illustrated by the abnormality of glucose homeostasis in the body, resulting in hyperglycemia. Although significant research attention has been devoted to the development of diabetes regimens, which demonstrates success in lowering blood glucose levels, their efficacies are unsustainable due to undesirable side effects such as weight gain and hypoglycemia. Over the years, heterocyclic scaffolds have been the basis of anti-diabetic chemotherapies; hence, in this review we consolidate the use of bioactive scaffolds, which have been evaluated for their biological response as inhibitors against their respective anti-diabetic molecular targets over the past five years (2012-2017). Our investigation reveals a diverse target set which includes; protein tyrosine phosphatase 1 B (PTP1B), dipeptidly peptidase-4 (DPP-4), free fatty acid receptors 1 (FFAR1), G protein-coupled receptors (GPCR), peroxisome proliferator activated receptor-γ (PPARγ), sodium glucose co-transporter-2 (SGLT2), α-glucosidase, aldose reductase, glycogen phosphorylase (GP), fructose-1,6-bisphosphatase (FBPase), glucagon receptor (GCGr) and phosphoenolpyruvate carboxykinase (PEPCK). This review offers a medium on which future drug design and development toward diabetes management may be modelled (i.e. optimization via structural derivatization), as many of the drug candidates highlighted show promise as an effective anti-diabetic chemotherapy.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores Enzimáticos/química , Frutose-Bifosfatase/antagonistas & inibidores , Frutose-Bifosfatase/metabolismo , Humanos , Hipoglicemiantes/química , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/antagonistas & inibidores , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glucagon/antagonistas & inibidores , Receptores de Glucagon/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose
6.
J Phys Chem B ; 121(6): 1186-1203, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-28084742

RESUMO

Selective monoamine oxidase-B (MAO-B) inhibitors are imperative in the treatment of various neurodegenerative disorders. Herein, we describe the pharmacophore generation and atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of previously reported thiophene-based hMAO-B inhibitors by our research group. The aim of this study was to identify the principal structural features that could potentially be responsible for the inhibitory activity of hMAO-B inhibitors. The best pharmacophore model generated was the four-point assay of AHRR.8. The pharmacophore model exhibited good correlation with its predictability of the statistically valid 3D-QSAR analyses. Density functional theory calculations were further employed on the lead molecule (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino) phenyl] prop-2-en-1-one (Tb5) to investigate the electrostatic potential surface and analyze the natural bond orbital toward the binding characteristics. Molecular dynamics simulations were performed to characterize the molecular level interactions and relative energies of the hMAO isoforms: hMAO-A and hMAO-B with three potent and selective hMAO-B inhibitors (Tb5, Tb6, and Tb9). The results of both continuous and accelerated molecular dynamics simulations demonstrate a distinct preference of the three ligands to bind to hMAO-B rather than hMAO-A.


Assuntos
Chalconas/farmacologia , Simulação de Dinâmica Molecular , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Relação Quantitativa Estrutura-Atividade , Teoria Quântica , Chalconas/química , Humanos , Inibidores da Monoaminoxidase/química
7.
Bioorg Med Chem Lett ; 27(3): 370-386, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28017531

RESUMO

Modern chemotherapy has significantly improved patient outcomes against drug-sensitive tuberculosis. However, the rapid emergence of drug-resistant tuberculosis, together with the bacterium's ability to persist and remain latent present a major public health challenge. To overcome this problem, research into novel anti-tuberculosis targets and drug candidates is thus of paramount importance. This review article provides an overview of tuberculosis highlighting the recent advances and tools that are employed in the field of anti-tuberculosis drug discovery. The predominant focus is on anti-tuberculosis agents that are currently in the pipeline, i.e. clinical trials.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose/dietoterapia , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , DNA Bacteriano/química , DNA Bacteriano/metabolismo , Descoberta de Drogas , Farmacorresistência Bacteriana/efeitos dos fármacos , Genômica , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológico
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