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1.
Cancer Invest ; : 1-16, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38966000

RESUMO

Currently, cervical cancer (CC) is the fourth recorded widespread cancer among women globally. There are still many cases of metastatic or recurring disease discovered, despite the incidence and fatality rates declining due to screening identification and innovative treatment approaches. Palliative chemotherapy continues to be the standard of care for patients who are not contenders for curative therapies like surgery and radiotherapy. This article seeks to provide a thorough and current summary of therapies that have been looked into for the management of CC. The authors emphasize the ongoing trials while reviewing the findings of clinical research. Agents that use biological mechanisms to target different molecular pathways such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribosepolymerase (PARP), and epigenetic biological mechanisms epitomize and offer intriguing research prospects.

2.
Plants (Basel) ; 13(11)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38891359

RESUMO

The foliar application of nutrients and plant growth regulators (PGRs) at critical crop growth periods can improve the yield of field crops. Hence, the present study was conducted to quantify the effects of the combined application of nutrients and PGRs (crop-specific formulation) on maize, blackgram, greengram, groundnut, cotton, sugarcane, and coconut yield. In all the crops except coconut, the treatments included (i) a foliar spray of crop-specific nutrients and PGR combinations and (ii) an unsprayed control. In coconut, the treatments included (i) the root feeding of coconut-specific nutrients and PGR combinations and (ii) an untreated control. Crop-specific nutrient and PGR formulations were sprayed, namely, Tamil Nadu Agricultural University (TNAU) maize maxim 1.5% at the tassel initiation and grain-filling stages of maize, TNAU pulse wonder 1.0% at the peak flowering stage of green gram and black gram, TNAU groundnut-rich 1.0% at the flowering and pod-filling stages of groundnut, TNAU cotton plus 1.25% at the flowering and boll development stages of cotton, and TNAU sugarcane booster 0.5% at 45 days after planting (DAP), 0.75% at 60 DAP, and 1.0% at 75 DAP of sugarcane. The results showed that the foliar application of TNAU maize maxim, TNAU pulse wonder, TNAU groundnut-rich, TNAU cotton plus and TNAU sugarcane booster and the root feeding of TNAU coconut tonic increased the yield of maize, pulses, groundnut, cotton, sugarcane, and coconut, resulting in higher economic returns.

3.
Mini Rev Med Chem ; 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38385496

RESUMO

Prostate cancer is a widespread malignancy among men, with a substantial global impact on morbidity and mortality. Despite advances in conventional therapies, the need for innovative and less toxic treatments remains a priority. Emerging evidence suggests that dietary plant metabolites possess epigenetic-modifying properties, making them attractive candidates for prostate cancer treatment. The present work reviews the epigenetic effects of dietary plant metabolites in the context of prostate cancer therapy. We first outline the key epigenetic mechanisms involved in prostate cancer pathogenesis, including histone modifications, DNA methylation, and miRNA or Long Noncoding RNA (lncRNA) dysregulation. Next, we delve into the vast array of dietary plant metabolites that have demonstrated promising anti-cancer effects through epigenetic regulation. Resveratrol, minerals, isothiocyanates, curcumin, tea polyphenols, soy isoflavones and phytoestrogens, garlic compounds, anthocyanins, lycopene, and indoles are among the most extensively studied compounds. These plant-derived bioactive compounds have been shown to influence DNA methylation patterns, histone modifications, and microRNA expression, thereby altering the gene expression allied with prostate cancer progression, cell proliferation, and apoptosis. We also explore preclinical and clinical studies investigating the efficacy of dietary plant metabolites as standalone treatments or in combination with traditional treatments for people with prostate cancer. The present work highlights the potential of dietary plant metabolites as epigenetic modulators to treat prostate cancer. Continued research in this field may pave the way for personalized and precision medicine approaches, moving us closer to the goal of improved prostate cancer management.

4.
Mini Rev Med Chem ; 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38343053

RESUMO

Chemotherapy is still the major method of treatment for many types of cancer. Curative cancer therapy is hampered significantly by medication resistance. Acidic organelles like lysosomes serve as protagonists in cellular digestion. Lysosomes, however, are gaining popularity due to their speeding involvement in cancer progression and resistance. For instance, weak chemotherapeutic drugs of basic nature permeate through the lysosomal membrane and are retained in lysosomes in their cationic state, while extracellular release of lysosomal enzymes induces cancer, cytosolic escape of lysosomal hydrolases causes apoptosis, and so on. Drug availability at the sites of action is decreased due to lysosomal drug sequestration, which also enhances cancer resistance. This review looks at lysosomal drug sequestration mechanisms and how they affect cancer treatment resistance. Using lysosomes as subcellular targets to combat drug resistance and reverse drug sequestration is another method for overcoming drug resistance that is covered in this article. The present review has identified lysosomal drug sequestration as one of the reasons behind chemoresistance. The article delves deeper into specific aspects of lysosomal sequestration, providing nuanced insights, critical evaluations, or novel interpretations of different approaches that target lysosomes to defect cancer.

5.
Curr Top Med Chem ; 24(6): 523-540, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38258788

RESUMO

Scientists are constantly researching and launching potential chemotherapeutic agents as an irreplaceable weapon to fight the battle against cancer. Despite remarkable advancement over the past several decades to wipe out cancer through early diagnosis, proper prevention, and timely treatment, cancer is not ready to give up and leave the battleground. It continuously tries to find some other way to give a tough fight for its survival, either by escaping from the effect of chemotherapeutic drugs or utilising its own chemical messengers like cytokines to ensure resistance. Cytokines play a significant role in cancer cell growth and progression, and the present article highlights their substantial contribution to mechanisms of resistance toward therapeutic drugs. Multiple clinical studies have even described the importance of specific cytokines released from cancer cells as well as stromal cells in conferring resistance. Herein, we discuss the different mechanism behind drug resistance and the crosstalk between tumor development and cytokines release and their contribution to showing resistance towards chemotherapeutics. As a part of this review, different approaches to cytokines profile have been identified and employed to successfully target new evolving mechanisms of resistance and their possible treatment options.


Assuntos
Antineoplásicos , Citocinas , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Citocinas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química
6.
Mini Rev Med Chem ; 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37861053

RESUMO

Cortisol, commonly known as the "stress hormone," plays a critical role in the body's response to stress. Elevated cortisol levels have been associated with various mental disorders, including anxiety, depression, and post-traumatic stress disorder. Consequently, researchers have explored cortisol modulation as a promising avenue for treating these conditions. However, the availability of research on cortisol as a therapeutic option for mental disorders is limited, and existing studies employ diverse methodologies and outcome measures. This review article aimed to provide insights into different treatment approaches, both pharmacological and non-pharmacological, which can effectively modulate cortisol levels. Pharmacological interventions involve the use of substances, such as somatostatin analogs, dopamine agonists, corticotropin-releasing hormone antagonists, and cortisol synthesis inhibitors. Additionally, non-pharmacological techniques, including cognitivebehavioral therapy, herbs and supplements, transcranial magnetic stimulation, lifestyle changes, and surgery, have been investigated to reduce cortisol levels. The emerging evidence suggests that cortisol modulation could be a promising treatment option for mental disorders. However, more research is needed to fully understand the effectiveness and safety of these therapies.

7.
Turk J Pharm Sci ; 20(4): 270-284, 2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37606012

RESUMO

The present study aimed to establish significant and validated quantitative structure-activity relationship (QSAR) models for histone deacetylase (HDAC) inhibitors and correlate their physicochemical, steric, and electrostatic properties with their anticancer activity. We have selected a dataset from earlier research findings. The target and ligand molecules were procured from recognized databases and incorporated into pivotal findings such as molecular docking (XP glide), e-pharmacophore study and 3D QSAR model designing study (phase). Docking revealed molecule 39 with better docking score and well binding contact with the protein. 3D QSAR analysis, which was performed for partial least squares factor 5 reported good 0.9877 and 0.7142 as R2 and Q2 values and low standard of deviation: 0.1049 for hypothesis AADRR.139. Based on the computational outcome, it has been concluded that molecule 39 is an effective and relevant candidate for inhibition of HDAC activity. Moreover, these computational approaches motivate to discover novel drug candidates in pharmacological and healthcare sectors.

8.
Curr Med Chem ; 30(24): 2762-2795, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36154583

RESUMO

Multi-targeted agents can interact with multiple targets sequentially, resulting in synergistic and more effective therapies for several complicated disorders, including cancer, even with relatively modest activity. Histone deacetylase (HDAC) inhibitors are low molecular weight small compounds that increase the acetylation of histone and nonhistone proteins, altering gene expression and thereby impacting angiogenesis, metastasis, and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular pathways thus producing adverse issues, causing therapeutic resistance, and they have poor pharmacokinetic properties. The designing of HDAC-based dual/multi-target inhibitor is an important strategy to overcome adverse effects, drug resistance and increase the effectiveness in controlling cancer. The selection of target combinations to design multitarget HDAC inhibitor is generally accomplished on the basis of systematic highthroughput screening (HTS), network pharmacology analysis methods. The identification of the pharmacophore against individual targets is performed using rational or computation methods. The identified pharmacophore can combine with merged, fused, or linked with the cleavable or non-cleavable linker to retain the interaction with the original target while being compatible with the other target. The objective of this review is to elucidate the potential targets' design strategies, biological activity, and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. This review elucidates the designing strategies of the potential target along with biological activity and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. The development of HDAC-based dual/multi-target inhibitors is important for overcoming side effects, drug resistance, and effective cancer control.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/metabolismo
9.
Curr Top Med Chem ; 22(22): 1849-1867, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36082857

RESUMO

BACKGROUND: The management of Alzheimer's disease is challenging due to its complexity. However, the currently approved and marketed treatments for this neurodegenerative disorder revolves around cholinesterase inhibitors, glutamate regulators, or the combination of these agents. Despite the prompt assurance of many new drugs, several agents were unsuccessful, especially in phase II or III trials, not meeting efficacy endpoints. OBJECTIVE: The execution of effective treatment approaches through further trials investigating a rational combination of agents is necessitude for Alzheimer's disease. METHODS: For this review, more than 248 relevant scientific papers were considered from a variety of databases (Scopus, Web of Science, Google Scholar, ScienceDirect, and PubMed) using the keywords Alzheimer's disease, amyloid-ß, combination therapies, cholinesterase inhibitors, dementia, glutamate regulators, AD hypothesis. RESULT AND DISCUSSION: The researcher's intent is to either develop a disease-modifying therapeutic means for aiming in the early phases of dementia and/or optimize the available symptomatic treatments principally committed to the more advanced stages of Alzheimer's. Since Alzheimer's possesses multifactorial pathogenesis, designing a multimodal therapeutic intervention for targeting different pathological processes of dementia may appear to be the most practical method to alter the course of disease progression. CONCLUSION: The combination approach may even allow for providing individual agents in lower doses, with reducible costs and side effects. Numerous studies on combination therapy predicted better clinical efficacy than monotherapy. The literature review highlights the major clinical studies (both symptomatic and disease-modifying) conducted in the past decade on combination therapy to combat cognitive disorder.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Peptídeos beta-Amiloides , Glutamatos/uso terapêutico
10.
J Genet Eng Biotechnol ; 20(1): 58, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35420322

RESUMO

BACKGROUND: The recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection cause high mortality and there is an emergency need to develop a specific drug to treat the novel coronavirus disease, COVID-19. However, some natural and synthetic products with action against SARS-CoV-2 have been reported in recent research, there is no specific drug available for treating COVID-19. In the present study, molecular interaction analysis was performed for 16 semisynthetic andrographolides (AGP) against 5 SARS-CoV-2 enzymes main protease (Mpro, PDB: 6LU7), papain-like protease (PLpro, PDB: 6WUU), spike glycoprotein (S, PDB: 6VXX), NSP15 endoribonuclease (NSP15, PDB: 6VWW), and RNA-dependent RNA polymerase (RdRp, PDB: 6M71). Moreover, the compounds pharmacokinetic and toxic profiles were also analyzed using computational tools. RESULTS: The protein-ligand docking score (kcal/mol) revealed that all the tested AGP derivatives showed a better binding affinity towards all the tested enzymes than hydroxychloroquine (HCQ). Meanwhile, all the tested AGP derivatives showed a better binding score with RdRp and S than remdesivir (REM). Interestingly, compounds 12, 14, and 15 showed a better binding affinity towards the all the tested enzyme than AGP, REM, and HCQ. AGP-16 had shown - 8.7 kcal/mol binding/docking score for Mpro, AGP-15 showed - 8.6 kcal/mol for NSP15, and AGP-10, 13, and 15 exhibited - 8.7, - 8.9, and - 8.7 kcal/mol, respectively, for S. CONCLUSION: Overall results of the present study concluded that AGP derivatives 14 and 15 could be the best 'lead' candidate for the treatment against SARS-CoV-2 infection. However, molecular dynamic studies and pharmacological screenings are essential to developing AGP derivatives 14 and 15 as a drug against COVID-19.

11.
Drug Discov Today ; 27(6): 1689-1697, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35183793

RESUMO

A significant impediment to the treatment of solid and nonsolid cancers is the decline of drug efficacy and/or occurrence of adverse effects. In recent years, there has been increasing interest in oncolytic viruses (OVs) as a method to treat cancer because of their specificity for cancerous tissue and reduced likelihood of adverse effects. The results of clinical trials suggest that OVs have an acceptable safety profile and are effective in treating certain types of cancer, despite the limited number of these organisms. However, further advances are needed to make oncolytic virotherapy more effective by increasing tumor permeation and improving virus delivery. Combining oncolytic virotherapy with conventional treatments, such as targeted inhibitory drugs (e.g., histone deacetylase inhibitors), could results in safer, more reliable, and more effective therapeutics.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos
12.
Artigo em Inglês | MEDLINE | ID: mdl-34751250

RESUMO

BACKGROUND: The World Health Organization (WHO) announced the COVID-19 occurrence as a global pandemic in March 2020. The treatment of SARS-CoV-2 patients is based on the experience gained from SARS-CoV and MERS-CoV infection during 2003. There is no clinically accepted therapeutic drug(s) accessible yet for the treatment of COVID-19. MAIN BODY: Corticosteroids, i.e., dexamethasone, methylprednisolone, hydrocortisone and prednisone are used alone or in combination for the treatment of moderate, severe and critically infected COVID-19 patients who are hospitalized and require supplemental oxygen as per current management strategies and guidelines for COVID-19 published by the National Institutes of Health. Corticosteroids are recorded in the WHO model list of essential medicines and are easily accessible worldwide at a cheaper cost in multiple formulations and various dosage forms. Corticosteroid can be used in all age group of patients, i.e., children, adult, elderly and during pregnancy or breastfeeding women. Corticosteroids have potent anti-inflammatory and immunosuppressive effects in both primary and secondary immune cells, thereby reducing the generation of proinflammatory cytokines and chemokines and lowering the activation of T cells, monocytes and macrophages. The corticosteroids should not be used in the treatment of non-severe COVID-19 patients because corticosteroids suppress the immune response and reduce the symptoms and associated side effects such as slow recovery, bacterial infections, hypokalemia, mucormycosis and finally increase the chances of death. CONCLUSION: Intensive research on corticosteroid therapy in COVID-19 treatment is urgently needed to elucidate their mechanisms and importance in contributing toward successful prevention and treatment approaches. Hence, this review emphasizes on recent advancement on corticosteroid therapy for defining their importance in overcoming SARS-CoV-2 pandemic, their mechanism, efficacy and extent of corticosteroids in the treatment of COVID-19 patients.

13.
Pharmaceuticals (Basel) ; 14(7)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34358089

RESUMO

A significant number of the anti-inflammatory drugs currently in use are becoming obsolete. These are exceptionally hazardous for long-term use because of their possible unfavourable impacts. Subsequently, in the ebb-and-flow decade, analysts and researchers are engaged in developing new anti-inflammatory drugs, and many such agents are in the later phases of clinical trials. Molecules with heterocyclic nuclei are similar to various natural antecedents, thus acquiring immense consideration from scientific experts and researchers. The arguably most adaptable heterocyclic cores are benzimidazoles containing nitrogen in a bicyclic scaffold. Numerous benzimidazole drugs are broadly used in the treatment of numerous diseases, showing promising therapeutic potential. Benzimidazole derivatives exert anti-inflammatory effects mainly by interacting with transient receptor potential vanilloid-1, cannabinoid receptors, bradykinin receptors, specific cytokines, 5-lipoxygenase activating protein and cyclooxygenase. Literature on structure-activity relationship (SAR) and investigations of benzimidazoles highlight that the substituent's tendency and position on the benzimidazole ring significantly contribute to the anti-inflammatory activity. Reported SAR analyses indicate that substitution at the N1, C2, C5 and C6 positions of the benzimidazole scaffold greatly influence the anti-inflammatory activity. For example, benzimidazole substituted with anacardic acid on C2 inhibits COX-2, and 5-carboxamide or sulfamoyl or sulfonyl benzimidazole antagonises the cannabinoid receptor, whereas the C2 diarylamine and C3 carboxamide substitution of the benzimidazole scaffold result in antagonism of the bradykinin receptor. In this review, we examine the insights regarding the SARs of anti-inflammatory benzimidazole compounds, which will be helpful for researchers in designing and developing potential anti-inflammatory drugs to target inflammation-promoting enzymes.

14.
Turk J Pharm Sci ; 18(2): 151-156, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33900700

RESUMO

Objectives: The present study aimed to establish significant and validated quantitative structure-activity relationship (QSAR) models for neuraminidase inhibitors and correlate their physicochemical, steric, and electrostatic properties with their anti-influenza activity. Materials and Methods: We have developed and validated 2D and 3D QSAR models by using multiple linear regression, partial least square regression, and k-nearest neighbor-molecular field analysis methods. Results: 2D QSAR models had q2: 0.950 and pred_r2: 0.877 and 3D QSAR models had q2: 0.899 and pred_r2: 0.957. These results showed that the models werere predictive. Conclusion: Parameters such as hydrogen count and hydrophilicity were involved in 2D QSAR models. The 3D QSAR study revealed that steric and hydrophobic descriptors were negatively contributed to neuraminidase inhibitory activity. The results of this study could be used as platform for design of better anti-influenza drugs.

15.
Mini Rev Med Chem ; 21(8): 1004-1016, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33280595

RESUMO

The novel coronavirus disease-19 (COVID-19) is a global pandemic that emerged from Wuhan, China, and has spread all around the world, affecting 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 updates of August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine exists. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID- 19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in clinical uses or studies on COVID-19 and also focuses on the mode of action of drugs being repositioned against COVID-19.


Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , COVID-19/virologia , Humanos , SARS-CoV-2/isolamento & purificação
16.
Future Oncol ; 16(30): 2457-2469, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32815411

RESUMO

HDAC inhibitors (HDACi) play an essential role in various cellular processes, such as differentiation and transcriptional regulation of key genes and cytostatic factors, cell cycle arrest and apoptosis that facilitates the targeting of epigenome of eukaryotic cells. In the majority of cancers, only a handful of patients receive optimal benefit from chemotherapeutics. Additionally, there is emerging interest in the use of HDACi to modulate the effects of ionizing radiations. The use of HDACi with radiotherapy, with the goal of reaching dissimilar, often distinct pathways or multiple biological targets, with the expectation of synergistic effects, reduced toxicity and diminished intrinsic and acquired resistance, conveys an approach of increasing interest. In this review, the clinical potential of HDACi in combination with radiotherapy is described as an efficient synergy for cancer treatment will be overviewed.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/terapia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Quimiorradioterapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/mortalidade , Tolerância a Radiação , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/uso terapêutico , Radioterapia Adjuvante , Resultado do Tratamento
17.
Curr Cancer Drug Targets ; 17(5): 456-466, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28067178

RESUMO

BACKGROUND: Colorectal cancer is a devastating disease with a dismal prognosis which is heavily hampered by delayed diagnosis. Surgical resection, radiation therapy and chemotherapy are the curative options. Due to few therapeutic treatments available i.e., mono and combination therapy and development of resistance towards drug response, novel and efficacious therapy are urgently needed. OBJECTIVE: In this study, we have studied the potential of histone deacetylase inhibitors in colorectal cancer. RESULTS: Histone deacetylase inhibitors (HDACIs) are an emerging class of therapeutic agents having potential anticancer activity with minimal toxicity for different types of malignancies in preclinical studies. HDACIs have proven less effective in monotherapy thus the combination of HDACIs with other anticancer agents are being assessed for the treatment of colorectal cancer. CONCLUSION: The molecular mechanism emphasizing the anticancer effect of HDACIs in colorectal cancer was illustrated and a recapitulation was carried out on the recent advances in the rationale behind combination therapies currently underway in clinical evaluations.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Camundongos Nus
18.
Comb Chem High Throughput Screen ; 19(9): 735-751, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27487787

RESUMO

BACKGROUND: Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. OBJECTIVE: To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. METHOD: The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. RESULTS: Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. CONCLUSION: The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.


Assuntos
Antineoplásicos/química , Simulação por Computador , Inibidores de Histona Desacetilases/química , Relação Quantitativa Estrutura-Atividade , Humanos , Simulação de Acoplamento Molecular , Interface Usuário-Computador
19.
Artigo em Inglês | MEDLINE | ID: mdl-27063392

RESUMO

Anticonvulsant refers to a group of pharmaceuticals used in the treatment of epileptic seizures. The use of current antiepileptic drugs has been questioned due to the non-selectivity of the drugs and the undesirable side effects produced by them. This led to the search for antiepileptic compounds with more selectivity and lower toxicity. Semicarbazones have been developed as versatile anticonvulsant pharmacophore. It has displayed potent anticonvulsant effect in a wide variety of preclinical anticonvulsant models. Till date various semicarbazone derivatives containing 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyrimidine, benzothiazole and substituted phenyl/aryl ring have been synthesized and evaluated for anticonvulsant activity. The semicarbazone based pharmacophore model with four binding sites is essential for anticonvulsant activity. This model comprises of an aryl hydrophobic binding site, hydrogen bonding domain, an electron donor group and another hydrophobic-hydrophilic site regulating the pharmacokinetic properties of the anticonvulsant. Extensive structure-activity relationship has demonstrated that compound with OH, CH3O, NO2, Cl, F, Br substituents in the arylhydrophobic pocket, nitro, hydroxy group on distant phenyl ring and a hydrogen bonding domain possess anticonvulsant activity. In this review, advances made in the application of semicarbazones as a versatile pharmacophore model for the design of new anticonvulsant drugs are being updated and suggested for future drug design and development of novel anticonvulsants.

20.
Artigo em Inglês | MEDLINE | ID: mdl-27026153

RESUMO

BACKGROUND: Epilepsy is a neurological disorder, characterized by seizures accompanied by loss or disturbance of consciousness affecting various physical and mental functions. Current anticonvulsant drugs are effective in controlling seizures in about 70% of cases, but their use is often limited by side effects like ataxia, megaloblastic anemia, hepatic failure. In search for a novel anticovulsant drug with better efficacy and lower toxicity, a series of novel pyrimidine based semicarbazone were designed and evaluated for antiepileptic activity. METHODS: The test compounds were designed on the basis of four site binding hypothesis proposed for anticonvulsant activity. The chemical structures of the test compounds were elucidated using spectral (IR, 1H NMR, 13C NMR and MS) and elemental analysis. The minimal motor impairment activity was determined in mice using rotorod test. The maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models were employed for anticonvulsant evaluation. RESULTS: The results reveal that 76% of the compounds were active in the MES screening as compared to 53% of the compounds in the scPTZ test. Test compounds showed some MES selectivity displaying their effectiveness in generalized seizures of the tonic-clonic type. The molecular docking analysis of semicarbazone derivatives showed good ligand-receptor interactions with specially hydrogen bond interactions with ARG192, GLU270 and THR353 amino acid of receptor. CONCLUSION: The present report confirms that pharmacophore model with four binding sites is crucial for anticonvulsant activity in the semicarbazones.

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