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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.
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Drogas em Investigação , Terapia de Alvo Molecular , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Feminino , Terapia de Alvo Molecular/métodos , Drogas em Investigação/uso terapêutico , Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
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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 TratamentoRESUMO
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.
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Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Lisossomos , Neoplasias , Humanos , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , AnimaisRESUMO
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.
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Epigênese Genética , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Epigênese Genética/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/químicaRESUMO
Globally, one of the most prevalent cancers is colorectal cancer (CRC). Chemotherapy and surgery are two common conventional CRC therapies that are frequently ineffective and have serious adverse effects. Thus, there is a need for complementary and different therapeutic approaches. The use of microbial metabolites to trigger epigenetic alterations as a way of preventing CRC is one newly emerging field of inquiry. Small chemicals called microbial metabolites, which are made by microbes and capable of altering host cell behaviour, are created. Recent research has demonstrated that these metabolites can lead to epigenetic modifications such as histone modifications, DNA methylation, and non-coding RNA regulation, which can control gene expression and affect cellular behaviour. This review highlights the current knowledge on the epigenetic modification for cancer treatment, immunomodulatory and anti-carcinogenic attributes of microbial metabolites, gut epigenetic targeting system, and the role of dietary fibre and gut microbiota in cancer treatment. It also focuses on short-chain fatty acids, especially butyrates (which are generated by microbes), and their cancer treatment perspective, challenges, and limitations, as well as state-of-the-art research on microbial metabolites-induced epigenetic changes for CRC inhibition. In conclusion, the present work highlights the potential of microbial metabolites-induced epigenetic modifications as a novel therapeutic strategy for CRC suppression and guides future research directions in this dynamic field.
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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.
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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/químicaRESUMO
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.
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Two novel series of N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide and N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide were synthesized to meet structural prerequisite indispensable for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. The rotorod test was conducted to evaluate neurotoxicity. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The outcome of the present investigations proved that the four binding sites pharmacophore model is vital for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among test compounds.
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Anticonvulsivantes/síntese química , Cicloexenos/química , Monoterpenos/química , Oxidiazóis/química , Semicarbazonas/química , Terpenos/química , Monoterpenos Acíclicos , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Sítios de Ligação , Cicloexenos/síntese química , Cicloexenos/farmacologia , Modelos Animais de Doenças , Limoneno , Monoterpenos/síntese química , Monoterpenos/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Convulsões/tratamento farmacológico , Semicarbazonas/síntese química , Semicarbazonas/farmacologia , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
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.
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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.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/metabolismoRESUMO
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.
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A linear quantitative structure activity relationship (QSAR) model is presented for predicting human immunodeficiency virus-1 (HIV-1) reverse transcriptase enzyme inhibition. The 2D QSAR and 3D-QSAR models were developed by stepwise multiple linear regression, partial least square (PLS) regression and k-nearest neighbor-molecular field analysis, PLS regression, respectively using a database consisting of 33 recently discovered benzoxazinones. The primary findings of this study is that the number of hydrogen atoms, number of (-NH2) group connected with solitary single bond alters the inhibition of HIV-1 reverse transcriptase. Further, presence of electrostatic, hydrophobic and steric field descriptors significantly affects the ability of benzoxazinone derivatives to inhibit HIV-1 reverse transcriptase. The selected descriptors could serve as a primer for the design of novel and potent antagonists of HIV-1 reverse transcriptase.
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Transcriptase Reversa do HIV/antagonistas & inibidores , DNA Polimerase Dirigida por RNA/química , DNA Polimerase Dirigida por RNA/farmacologia , Análise dos Mínimos Quadrados , Modelos Moleculares , Relação Quantitativa Estrutura-AtividadeRESUMO
The incomplete seizure control with frequent adverse effects of current anticonvulsant drugs and the importance of semicarbazones, quinazolines and 2,5-disubstituted 1,3,4-thiadiazoles as anticonvulsant pharmacophore prompted us to carry out synthesis of three novel series of semicarbazones containing 1,3,4-thiadiazole and quinazoline ring. The chemical structures of these compounds were elucidated by elemental and spectral (IR, 1H NMR, 13C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The rotorod test was conducted to evaluate neurotoxicity. The majority of the compounds were found active in the biological screening. The outcome of the present investigations proved that the four binding sites pharmacophore model is decisive for antiepileptic activity. An attempt has also been performed to establish structure-activity relationships among synthesized compounds.
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Anticonvulsivantes/síntese química , Quinazolinas/síntese química , Tiadiazóis/síntese química , Animais , Anticonvulsivantes/farmacologia , Camundongos , Quinazolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiadiazóis/farmacologiaRESUMO
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.
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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.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Peptídeos beta-Amiloides , Glutamatos/uso terapêuticoRESUMO
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.
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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/métodosRESUMO
The enzymatic inhibition of histone deacetylase activity has come out as a novel and effectual means for the treatment of cancer. Two novel series of 2-[5-(4-substitutedphenyl)-[1,3,4]-oxadiazol/thiadiazol-2-ylamino]-pyrimidine-5-carboxylic acid (tetrahydro-pyran-2-yloxy)-amides were designed and synthesized as novel hydroxamic acid based histone deacetylase inhibitors. The antiproliferative activities of the compounds were investigated in vitro using histone deacetylase inhibitory assay and MTT assay. The synthesized compounds were also tested for antitumor activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present studying indicates 2,5-disubstituted 1,3,4-oxadiazole/thiadiazole as promising surface recognition moiety for development of newer hydroxamic acid based histone deacetylase inhibitor.
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Antineoplásicos/química , Antineoplásicos/síntese química , Desenho de Fármacos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Oxidiazóis/química , Tiadiazóis/química , Animais , Antineoplásicos/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Proliferação de Células , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/química , Camundongos , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Propriedades de Superfície , Zinco/químicaRESUMO
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.
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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.
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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.