RESUMO
In continuation of our previous work on cancer and inflammation, 15 novel pyrazole-pyrazoline hybrids (WSPP1-15) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in 1 H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (HA , HM , and HX ) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF-7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5-Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC50 values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC50 value of more than 50 µM. The derivatives were also evaluated for their in vitro anti-inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti-inflammatory activities were further studied for COX-2 inhibition. The manifestation of a higher COX-2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX-2 also exhibited a better spectrum of activity against various cancer cell lines.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Neoplasias/tratamento farmacológico , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Fluoruracila/farmacologia , Humanos , Concentração Inibidora 50 , Neoplasias/patologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Cancer remains considered as one of the leading global health problems either due to meagre and suboptimal therapeutic response of chemotherapeutic agents or due to the emergence of spontaneous complex multidrug resistance in cancer cells. This created a persistent need for the development of new anticancer agents. Enthralled by the high success rate for natural product-based drug discovery and current research scenario, we synthesized a new series of 3,4,5-trimethoxy phenyl ring pendant sulfur-containingcyanopyrimidine derivatives clubbed with different amines intending to search an anticancer lead compound. To probe the anti-proliferative spectrum of the synthesized derivatives, an in-vitro evaluation was piloted against a panel of 60 cancer cell lines at the National Cancer Institute (NCI) representing major types of cancer diseases. Most of the derivatives showed good to moderate anti-proliferative activity. The results revealed that compound 4e displayed the most promising broad-spectrum anticancer activity with high growth inhibition of various cell lines representing multiple cancers diseases. Mechanistic investigation of compound 4e in human breast cancer MDA-MB-231 cells showed that compound 4e triggers cell death through the induction of apoptosis. ADMET studies and reverse screening were also performed to identify the potential targets of designed molecules. It was concluded that 3,4,5-trimethoxy phenyl ring pendant sulfur-containingcyanopyrimidine derivative 4e could act as a promising hit molecule for further development of novel anticancer therapeutics.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pirimidinas/farmacologia , Enxofre/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Madin Darby de Rim Canino/efeitos dos fármacos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Enxofre/químicaRESUMO
In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a-r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a-r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC50 values were found to be 33.3⯱â¯1.68, 40.1⯱â¯1.0 and 19.0⯱â¯1.47⯵g/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC50 of 44.2⯱â¯2.72, 66.8⯱â¯2.05 and 73.1⯱â¯1.69⯵g/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.
Assuntos
Antimaláricos/farmacologia , Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Oxidiazóis/química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/metabolismo , Antiprotozoários/síntese química , Antiprotozoários/química , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Concentração Inibidora 50 , Leishmania/fisiologia , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Camundongos , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Estrutura Terciária de Proteína , Pirazóis/química , Células RAW 264.7 , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Depravity of malaria in terms of morbidity and mortality in human beings makes it a major health issue in tropical and subtropical areas of the globe. Drug counterfeiting and non-adherence to the treatment regimen have significantly contributed to development and spread of multidrug resistance that has highlighted the need for development of novel and more efficient antimalarial drugs. Complexity associated with cancer disease and prevalence of diversified cell populations vindicates highly specific treatment options for treatment of cancer. Resistance to these anticancer agents has posed a great hindrance in successful treatment of cancer. Pondering this ongoing situation, it was speculated to develop novel compounds targeting malaria and cancer. Moving on the same aisle, we synthesized pyrazole acrylic acid based oxadiazole and amide derivatives using multi-step reaction pathways (6a-x; 6a'-h'). Schizont maturation inhibition assay was employed to determine antimalarial potential. Compound 6v emerged as the most potent antimalarial agent targeting falcipain-2 enzyme. Anticancer activity was done using sulforhodamine B assay. Compounds 6b' and 6g' demonstrated promising results against all the tested cell lines. Further, Microscopic view clearly indicated formation of apoptotic bodies, chromatin condensation, shrinkage of cells and bleb formation. Validation of the results was achieved using molecular docking studies. From the obtained results, it was observed that cyclization (oxadiazole) favored antimalarial activity while non-cyclized compounds (amides) emerged as better anticancer agents.
Assuntos
Acrilatos/farmacologia , Amidas/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Oxidiazóis/farmacologia , Pirazóis/farmacologia , Acrilatos/química , Amidas/síntese química , Amidas/química , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Glucocorticoids are known to have vital effects on metabolism, behavior and immunity. Any sort of impairment in their synthesis may lead to the generation of numerous ill health effects. Different environmental toxicants, including bisphenols and their analogs pose deleterious effect on the biosynthesis of glucocorticoids, thereby leading to endocrine disruption. In order to assess the effect of these environmental toxicants on gluocorticoid biosynthetic pathway, an in silico study was performed. This involved molecular docking studies of 18 ligands with the selected participating enzymes of the pathway. These enzymes were CYP11A1, CYP11B2, CYP19A1, CYP17A1, 3α/20ß-HSD, 3ß/17ß-HSD and CYP21A2. Comparison of their binding affinity was made with the known inhibitors of these enzymes. In case of CYP11A1, Bisphenol M (BP M) had the lowest docking score (D score) of -8.699 kCal/mol, and was better than that of the standard, Metyrapone. Bisphenol PH (BP PH) was found to have significant affinity with CYP11B2. In case CYP19A1, results were found to be comparable with the standards, Exemestane and Letrozole. BP PH elicited better results than the standard Abiraterone acetate against CYP17A1. BP M had a D score of -7.759 against 3α/20ß-HSD, again better results than the standard, Trilostane. Upon molecular docking of BP PH against CYP21A2, it was seen that amongst all the analogs, it had maximum interactions along with the lowest D score. From all the above instances mentioned, it is quite evident that certain BPA analogs have more potential to modulate the enzymes involved in comparison to the known inhibitors.
Assuntos
Compostos Benzidrílicos/toxicidade , Inibidores das Enzimas do Citocromo P-450/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Glucocorticoides/biossíntese , Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Simulação de Acoplamento Molecular , Fenóis/toxicidade , Compostos Benzidrílicos/química , Compostos Benzidrílicos/metabolismo , Sítios de Ligação , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/química , Disruptores Endócrinos/química , Disruptores Endócrinos/metabolismo , Poluentes Ambientais/química , Poluentes Ambientais/metabolismo , Hidroxiesteroide Desidrogenases/química , Hidroxiesteroide Desidrogenases/metabolismo , Ligantes , Fenóis/química , Fenóis/metabolismo , Ligação Proteica , Conformação Proteica , Medição de Risco , Relação Estrutura-AtividadeRESUMO
Dioxins and dioxin-like compounds (DLCs) are known to cause endocrine disruption in humans and animals. Being lipophilic xenobiotic chemicals, they can be easily absorbed into the biological system from the surrounding environments, thereby causing various health dysfunctions. In the present study, a total of 100 dioxins and DLCs were taken, and their binding pattern was assessed with the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in comparison with the corresponding known inhibitors and a well-studied endocrine disrupting xenobiotic, bisphenol A (BPA). The nuclear receptors CAR and PXR are known to play a significant role in handling potential toxins by coordinating cellular transport and metabolic functions of the same. Among different endocrine-disrupting chemicals used in the present study, DLCs (PCDFs and PCBs) elicited better interactions in comparison with the parent dioxin (polychlorinated dibenzodioxins) compounds. On comparing D scores of all the compounds against both the receptors, PCDF 8-hydroxy-3,4-dichlorodibenzofuran (8-OH-DCDF) and PCB tetrachlorobenzyltoluene (TCBT) exhibited significant molecular interactions against PXR (-7.633 kcal mol-1 ) and CAR (-8.389 kcal mol-1 ), respectively. Predominant interactions were found to be H-bonding, π-π stacking, hydrophobic, polar, and van der Waals. By contrast, BPA and some natural ligands tested in this study showed lower binding affinities with these receptors than certain DLCs reported herein, ie, certain DLCs might be more toxic than the proven toxic agent, BPA. Such studies play a pivotal role in the risk assessment of exposure to dioxins and DLCs on human health.
Assuntos
Simulação por Computador , Dioxinas e Compostos Semelhantes a Dioxinas/química , Dioxinas e Compostos Semelhantes a Dioxinas/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Medição de Risco , Biocatálise , Receptor Constitutivo de Androstano , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Receptor de Pregnano X , Receptores de Esteroides/química , Reprodutibilidade dos TestesRESUMO
Dioxins and dioxin-like compounds (DLCs) are the ones with poor water solubility and low volatility, resistant to physical, chemical and biological processes, persistent in the environment even under extreme conditions. Due to lipophilic nature, they get adhered to the fatty material and concentrate through biomagnification and bioaccumulation, thereby easily getting incorporated into food chains, paving the way to endocrine disruption via modulation of various human receptors. This in turn leads to certain adverse health effects. In the present study, a total of 100 dioxins and DLCs were taken and their binding pattern was assessed with the ketosteroid receptors, i.e. androgen (hAR), glucocorticoid (hGR), progesterone (hPR) and mineralocorticoid (hMR) in comparison to the corresponding natural steroids and a known endocrine disrupting xenobiotic, Bisphenol A (BPA). Most of the DLCs, particularly those bearing hydroxyl (-OH) group showed considerable affinities with ketosteroid receptors. On comparing D scores of all the dioxins and DLCs against all four receptors, compound 8-hydroxy-3,4-dichlorodibenzofuran(8-OH-DCDF) exhibited least D score of -9.549 kcal mol-1 against hAR. 3,8-Dihydroxy-2-chlorodibenzofuran(3,8-DiOH-CDF), 4'-hydroxy-2,3,4,5-tetrachlorobiphenyl (4'-OH-TCB) and 4-hydroxy-2,2',5'-trichlorobiphenyl(4-OH-TCB) also showed comparable molecular interactions with the ketosteroid receptors. These interactions mainly include H-bonding, π-π stacking, hydrophobic, polar and van der Waals' interactions. In contrast, BPA and some natural ligands tested in this study showed lower binding affinities with these receptors than certain DLCs reported herein, i.e. certain DLCs might be more toxic than the proven toxic agent, BPA. Such studies play a pivotal role in the risk assessment of exposure to dioxins and DLCs on human health.
Assuntos
Dioxinas/química , Disruptores Endócrinos/química , Cetosteroides/química , Receptores de Esteroides/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Reprodutibilidade dos Testes , Medição de RiscoRESUMO
One of the most viable options to tackle the growing resistance to the antimalarial drugs is hybrid molecules. It involves combination of different scaffolds in one frame that may lead to compounds with diverse biological profiles. In this context, new hybrids of three different scaffolds viz pyrazole, pyrazoline and thiosemicarbazone moiety were incorporated into one single compound and evaluated for their in vitro schizontocidal activity against the CQ-sensitive 3D7 strain of Plasmodium falciparum. Compounds with significant in vitro antimalarial activity were further evaluated for cytotoxicity against VERO cell lines. The best active compound 48 exhibited an IC50 of 1.13 µM. The in vitro results were further validated by quantitative structure-activity relationship (QSAR).
Assuntos
Antimaláricos/farmacologia , Pirazóis/farmacologia , Tioamidas/química , Animais , Antimaláricos/síntese química , Antimaláricos/química , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/química , Relação Quantitativa Estrutura-AtividadeRESUMO
Alzheimer's disease (AD) presents a complex pathology involving amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Oxidative stress exacerbates AD progression through pathways like macromolecular peroxidation, mitochondrial dysfunction, and metal ion redox potential alteration linked to amyloid-beta (Aß). Despite limited approved medications, heterocyclic compounds have emerged as promising candidates in AD drug discovery. This review highlights recent advancements in synthetic heterocyclic compounds targeting oxidative stress, mitochondrial dysfunction, and neuroinflammation in AD. Additionally, it explores the potential of nanomaterial-based drug delivery systems to overcome challenges in AD treatment. Nanoparticles with heterocyclic scaffolds, like polysorbate 80-coated PLGA and Resveratrol-loaded nano-selenium, show improved brain transport and efficacy. Micellar CAPE and Melatonin-loaded nano-capsules exhibit enhanced antioxidant properties, while a tetra hydroacridine derivative (CHDA) combined with nano-radiogold particles demonstrates promising acetylcholinesterase inhibition without toxicity. This comprehensive review underscores the potential of nanotechnology-driven drug delivery for optimizing the therapeutic outcomes of novel synthetic heterocyclic compounds in AD management. Furthermore, the inclusion of various promising heterocyclic compounds with detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) data provides valuable insights for planning the development of novel drug delivery treatments for AD.
Assuntos
Doença de Alzheimer , Sistemas de Liberação de Medicamentos , Estresse Oxidativo , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Animais , Nanoestruturas/administração & dosagem , Compostos Heterocíclicos/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Nanopartículas/administração & dosagemRESUMO
Cancer stem cells (CSCs) have become a key player in the growth of tumors, the spread of cancer, and the resistance to therapeutic interventions. Targeting these elusive cell populations has the potential to fundamentally alter cancer treatment plans. CSCs, also known as tumor-initiating cells (TICs), are thought to play a role in both medication resistance and cancer recurrence. This is explained by their capacity to regenerate themselves and change into different kinds of cancer cells. Due to their higher expression of ATP-binding cassette (ABC) membrane transporters, enhanced epithelial to mesenchymal (EMT) characteristics, improved immune evasion, activation of survival signaling pathways, and improved DNA repair mechanisms, CSCs exhibit extraordinary resistance to therapies. This comprehensive analysis delves into advancements in the domain of Targeted Cancer Stem Cell Therapeutics, concentrating on unraveling the distinctive traits of CSCs and the therapeutic methods devised to eliminate them.
RESUMO
OBJECTIVE: To investigate the effects of Alogliptin in chemical-induced post-menopausal osteoporosis. METHODOLOGY: The binding affinity of alogliptin with osteogenic proteins was analysed in silico. The effect of alogliptin on osteogenic proteins and mineralization of osteoblastic cells was evaluated in UMR-106 cells. Further, in vivo anti-osteoporotic activity of alogliptin was evaluated in postmenopausal osteoporosis. Various bone turnover markers were assayed in serum. This followed the analysis of microarchitecture of bone, histology, and immunohistochemistry (IHC) of bone tissue. RESULTS: Docking scores showed that alogliptin has binding affinity for bone alkaline phosphatase (BALP), osteocalcin, and bone morphogenic protein (BMP-2). Alogliptin also enhanced mineralization of osteoblast cells, evidenced with increased ALP, osteocalcin, and BMP-2. Animal studies revealed significant elevation of bone formation markers, bone ALP, osteocalcin and BMP-2, and decreased bone resorption markers, receptor activator of NF-κß (RANKL), cathepsin K (CTSK), tartrate resistant acid phosphatase (TRAcP5b) in VCD-induced post-menopausal osteoporosis. Micro computed tomography (µCT) analysis and histology of femur bone and lumbar vertebrae demonstrated decrease in trabecular separation and improved bone density. IHC of femur showed reduced DPP4 enzyme. CONCLUSIONS: Alogliptin increased mineralization in osteoblast cells. It had beneficial effects also altered bone turnover markers, repaired the trabecular microstructure, improved bone mineral density, and exhibited bone forming capacity targeting DPP-4 enzyme in postmenopausal osteoporosis.
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AT1 receptor blockers (ARBs) are commonly used drugs to treat cardiovascular disease and hypertension, but research on their impact on brain disorders is unattainable. Valsartan (VAL) is a drug that specifically blocks AT1 receptor. Despite the previous evidence for VAL to provide neuroprotection in case of ischemic reperfusion injury, evaluation of their potential in mitigating mitochondrial dysfunction that causes neuronal cell death and neurobehavioral impairment remains unknown. The aim of this study was to evaluate the therapeutic effect of repurposed drug VAL against ischemic reperfusion injury-induced neuronal alternation. tMCAO surgery was performed to induce focal cerebral ischemic reperfusion injury. Following ischemic reperfusion injury, we analyzed the therapeutic efficacy of VAL by measuring the infarct volume, brain water content, mitochondrial oxidative stress, mitochondrial membrane potential, histopathological architecture, and apoptotic marker protein. Our results showed that VAL administrations (5 and 10 mg/kg b.wt.) mitigated the brain damage, enhanced neurobehavioral outcomes, and alleviated mitochondrial-mediated oxidative damage. In addition to this, our findings demonstrated that VAL administration inhibits neuronal apoptosis by restoring the mitochondrial membrane potential. A follow-up investigation demonstrated that VAL induces BDNF expression and promoted ischemic tolerance via modulating the Akt/p-Creb signaling pathway. In summary, our results suggested that VAL administration provided neuroprotection, ameliorated mitochondrial dysfunction, preserved the integrity of neurons, and lead to functional improvement after ischemic reperfusion injury.
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A series of pyrazolo[3,4-b]quinolines have been synthesized using one-pot water mediated synthetic route under microwave irradiation involving the condensation of 2-chloroquinoline-3-carbaldehydes with semicarbazide or 2,4-dinitrophenyl hydrazine. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. The pharmacological evaluation showed that the compounds are good at inhibiting edema induced by carrageenan and also showed prominent analgesic activity with lesser GI toxicity as indicated by severity index and LPO values.
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios/síntese química , Micro-Ondas , Pirazóis/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Pirazóis/farmacologia , Pirazóis/toxicidade , Ratos , Ratos WistarRESUMO
Quinoline or 1-aza-naphthalene is a weak tertiary base. Quinoline ring has been found to possess antimalarial, anti-bacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, and analgesic activity. Quinoline not only has a wide range of biological and pharmacological activities but there are several established protocols for the synthesis of this ring. The article aims at highlighting these very diversities of the ring.
RESUMO
Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis eleganshas beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
Assuntos
Doença de Alzheimer , Doença de Huntington , Doenças Neurodegenerativas , Doença de Parkinson , Animais , Humanos , Doenças Neurodegenerativas/genética , Caenorhabditis elegans/metabolismo , Doença de Alzheimer/genética , Doença de Huntington/genéticaRESUMO
Learning and memory storage are the fundamental activities of the brain. Aberrant expression of synaptic molecular markers has been linked to memory impairment in AD. Aging is one of the risk factors linked to gradual memory loss. It is estimated that approximately 13 million people worldwide will have AD by 2050. A massive amount of oxidative stress is kept under control by a complex network of antioxidants, which occasionally fails and results in neuronal oxidative stress. Increasing evidence suggests that ROS may affect many pathological aspects of AD, including Aß accumulation, tau hyperphosphorylation, synaptic plasticity, and mitochondrial dysfunction, which may collectively result in neurodegeneration in the brain. Further investigation into the relationship between oxidative stress and AD may provide an avenue for effective preservation and pharmacological treatment of this neurodegenerative disease. In this review, we briefly summarize the cellular mechanism underlying Aß induced synaptic dysfunction. Since oxidative stress is common in the elderly and may contribute to the pathogenesis of AD, we also shed light on the role of antioxidant and inflammatory pathways in oxidative stress adaptation, which has a potential therapeutic target in neurodegenerative diseases.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Idoso , Doença de Alzheimer/metabolismo , Estresse Oxidativo/fisiologia , Antioxidantes/metabolismo , Plasticidade Neuronal , Biomarcadores/metabolismo , Peptídeos beta-Amiloides/metabolismoRESUMO
Alzheimer's disease (AD) has been recognized as the most important cause of dementia, which is estimated to contribute more than 2 trillion USD in medical costs. AD patients encounter progressive neurodegenerative dementia associated with behavioural, linguistic, and visuospatial deficits. Although studies on the discovery of amyloid ß (Aß) and tau (the essential elements of plaques and tangles in AD) have shed light on the molecular pathological processes of AD, the exact cause of the condition is still largely unknown. The involvement of various proteins, such as amyloid-ß, prion protein, tau, and α-synuclein has been linked to AD pathogenesis. The current AD treatments are mainly based on symptomatic management and restoration of neurotransmitters' balance. There is a significant need to develop medications that can alter the underlying disease process and prevent its progression. The present manuscript provides a review of various hypotheses that have been proposed for AD pathogenesis. The manuscript has also explored the development of novel anti-AD drugs based on various pathogenic pathways, which are recently under various clinical trial phases.
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Parkinson's disease (PD) is the second most common neurodegenerative disorder; however, its etiology remains elusive. Antioxidants are considered to be a promising approach for decelerating neurodegenerative disease progression owing to extensive examination of the relationship between oxidative stress and neurodegenerative diseases. In this study, we investigated the therapeutic effect of melatonin against rotenone-induced toxicity in the Drosophila model of PD. The 3-5 day old flies were divided into four groups: control, melatonin alone, melatonin and rotenone, and rotenone alone groups. According to their respective groups, flies were exposed to a diet containing rotenone and melatonin for 7 days. We found that melatonin significantly reduced the mortality and climbing ability of Drosophila because of its antioxidative potency. It alleviated the expression of Bcl 2, tyrosine hydroxylase (TH), NADH dehydrogenase, mitochondrial membrane potential, and mitochondrial bioenergetics and decreased caspase 3 expression in the Drosophila model of rotenone-induced PD-like symptoms. These results indicate the neuromodulatory effect of melatonin, and that it is likely modulated against rotenone-induced neurotoxicity by suppressing oxidative stress and mitochondrial dysfunctions.
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Coronavirus disease (COVID-19) was reported to be transmitted from bats to humans and, became a pandemic in 2020. COVID-19 is responsible for millions of deaths worldwide and still, the numbers are increasing. Further, despite the availability of vaccines, mutation in the virus continuously poses a threat of re-emergence of the more lethal form of the virus. So far, the repurposing of drugs has been exercised heavily for the identification of therapeutic agents against COVID-19, which led FDA to approve many drugs for the same e.g., remdesivir, favipiravir, ribavirin, etc. The anti-COVID drugs explored via other approaches include nirmatrelvir (used in combination with ritonavir as Paxlovid), tixagevimab and cilgavimab (both used in combination with each other) and others. However, these approved drugs failed to achieve a significant clinical outcome. Globally, natural bioactive have also been explored for anti-COVID-19 effects, based on their traditional medicinal values. Although the clinical findings suggest that FDA-approved drugs and natural bioactives can help reducing the overall mortality rate but the significant clinical outcome was not achieved. Therefore, the focus has been shifted towards new drug development. In line with that, a lot of work has been done and still going on to explore heterocyclic compounds as potent anti- COVID-19 drugs. Several heterocyclic scaffolds have been previously reported with potent antiinflammatory, anticancer, anti-viral, antimicrobial and anti-tubercular effects. Few of them are under consideration for clinical trials whereas others are under preclinical investigation. Hence, this review discusses the evidence of rationally designed and tested heterocyclic compounds acting on different targets against COVID-19. The present article will help the researches and will serve as a pivotal resource in the design and development of novel anti-COVID-19 drugs.
Assuntos
COVID-19 , Compostos Heterocíclicos , Humanos , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêuticoRESUMO
A series of dihydro-pyrimidine-5-carbonitrile derivatives (3-16) were synthesized and evaluated for their anticonvulsant activity against MES and scPTZ models. Motor impairment screening was carried out by rotarod test method and CNS depressant effect was determined by Porsolt's force swim pool method. Compounds 4 and 9 having p-substituted bromo and m-substituted nitro groups, respectively, were found to be most active showing activity both in MES and scPTZ screen at lower doses of 30 mgkg(-1) at 0.5 h and 100 mgkg(-1) at 4 h. In the rotarod motor impairment screen, compound 4 did not show any motor impairment even at the maximum dose of 300 mgkg(-1); however, compound 9 showed motor impairment at 300 mgkg(-1) dose after 4.0 h. The compounds were also tested for their CNS depression effect. The compounds 4 and 9 showed 41.38 and 43.44% increase in immobility time with respect to control. The pharmacophore hypothesis also fits best for compounds 4 and 9.