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1.
Bioorg Med Chem ; 113: 117925, 2024 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-39357433

RESUMEN

Alzheimer's disease (AD) is a complex disorder that is influenced by a number of variables, such as age, gender, environmental factors, disease, lifestyle, infections, and many more. The main characteristic of AD is the formation of amyloid plaque and neurofibrillary tangles (NFT), which are caused by various reasons such as inflammation, impairment of neurotransmitters, hyperphosphorylation of tau protein, generation of toxic amyloid beta (Aß) 40/42, oxidative stress, etc. Protein kinases located in chromosome 21, namely dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A), play an essential role in the pathogenesis of AD. DYRK1A stimulates the Aß peptide aggregation and phosphorylation of tau protein to generate the NFT formation that causes neurodegeneration. Thus, DYRK1A is associated with AD, and inhibition of DYRK1A has the potential to treat AD. In this review, we discussed the pathophysiology of AD, various factors responsible for AD, and the role of DYRK1A in AD. We have also discussed the latest therapeutic potential of DYRK1A inhibitors for neurogenerative disease, along with their structure-activity relationship (SAR) studies. This article provides valuable information for guiding the future discovery of novel and target-specific DYRK1A inhibitors over other kinases and their structural optimization to treat AD.


Asunto(s)
Enfermedad de Alzheimer , Quinasas DyrK , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Animales , Relación Estructura-Actividad , Estructura Molecular , Fosforilación/efectos de los fármacos
2.
Bioorg Med Chem ; 74: 117047, 2022 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-36265268

RESUMEN

Alzheimer's disease (AD) is an irreversible, progressive neurological disorder characterized by amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neuronal damage, memory loss, etc. Various factors, such as age, lifestyle, family history, environmental factors, and gene mutation, cause AD. BACE-1 is an interesting target to prevent or reverse AD progression. BACE-1 cleaves amyloid precursor protein (APP) into soluble amyloid precursor protein ß (sAPPß) and membrane-bound C-terminal fragment called C99, a rate-limiting step, and C99 is further cleaved by gamma-secretase to generate neurotoxic amyloid ß (Aß). Discovery and development of selective ß amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors have a great potential for the treatment and maintenance of Alzheimer's disease. In this review, we have compiled literature pertaining to guanidine-based novel BACE-1 inhibitors for the treatment and maintenance of AD. We have also discussed role of BACE-1 substrates, and its crystal structure, BACE-1 inhibitors in the clinical trial, and essential points to overcome challenges associated with selective development of BACE-1 inhibitors. This paper provides valuable information for the design and discovery of selective new BACE-1 inhibitors against other aspartyl protease enzymes to treat AD.


Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Guanidina , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Inhibidores Enzimáticos/farmacología
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-34360945

RESUMEN

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.


Asunto(s)
Autofagia , COVID-19/metabolismo , Mitocondrias/metabolismo , Mitocondrias/virología , Animales , Autofagia/efectos de los fármacos , Humanos , Dinámicas Mitocondriales/efectos de los fármacos , Mitofagia/efectos de los fármacos , Virosis/tratamiento farmacológico , Virosis/metabolismo , Tratamiento Farmacológico de COVID-19
4.
Recent Pat Anticancer Drug Discov ; 19(3): 280-297, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37070439

RESUMEN

Highly proliferating cells, such as cancer cells, are in high demand of pyrimidine nucleotides for their proliferation, accomplished by de novo pyrimidine biosynthesis. The human dihydroorotate dehydrogenase (hDHODH) enzyme plays a vital role in the rate-limiting step of de novo pyrimidine biosynthesis. As a recognised therapeutic target, hDHODH plays a significant role in cancer and other illness. In the past two decades, small molecules as inhibitors hDHODH enzyme have drawn much attention as anticancer agents, and their role in rheumatoid arthritis (RA), and multiple sclerosis (MS). In this patent review, we have compiled patented hDHODH inhibitors published between 1999 and 2022 and discussed the development of hDHODH inhibitors as anticancer agents. Therapeutic potential of small molecules as hDHODH inhibitors for the treatment of various diseases, such as cancer, is very well recognised. Human DHODH inhibitors can rapidly cause intracellular uridine monophosphate (UMP) depletion to produce starvation of pyrimidine bases. Normal cells can better endure a brief period of starvation without the side effects of conventional cytotoxic medication and resume synthesis of nucleic acid and other cellular functions after inhibition of de novo pathway using an alternative salvage pathway. Highly proliferative cells such as cancer cells do not endure starvation because they are in high demand of nucleotides for cell differentiation, which is fulfilled by de novo pyrimidine biosynthesis. In addition, hDHODH inhibitors produce their desired activity at lower doses rather than a cytotoxic dose of other anticancer agents. Thus, inhibition of de novo pyrimidine biosynthesis will create new prospects for the development of novel targeted anticancer agents, which ongoing preclinical and clinical experiments define. Our work brings together a comprehensive patent review of the role of hDHODH in cancer, as well as various patents related to the hDHODH inhibitors and their anticancer and other therapeutic potential. This compiled work on patented DHODH inhibitors will guide researchers in pursuing the most promising drug discovery strategies against the hDHODH enzyme as anticancer agents.


Asunto(s)
Antineoplásicos , Neoplasias , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Humanos , Dihidroorotato Deshidrogenasa , Patentes como Asunto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Pirimidinas/uso terapéutico
5.
Expert Opin Ther Pat ; 33(9): 579-596, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37942637

RESUMEN

INTRODUCTION: Pyrimidine nucleotides are essential for the parasite's growth and replication. Parasites have only a de novo pathway for the biosynthesis of pyrimidine nucleotides. Dihydroorotate dehydrogenase (DHODH) enzyme is involved in the rate-limiting step of the pyrimidine biosynthesis pathway. DHODH is a biochemical target for the discovery of new antimalarial agents. AREA COVERED: This review discussed the development of patented PfDHODH inhibitors published between 2007 and 2023 along with their chemical structures and activities. EXPERT OPINION: PfDHODH enzyme is involved in the rate-limiting fourth step of the pyrimidine biosynthesis pathway. Thus, inhibition of PfDHODH using species-selective inhibitors has drawn much attention for treating malaria because they inhibit parasite growth without affecting normal human functions. Looking at the current scenario of antimalarial drug resistance with most of the available antimalarial drugs, there is a huge need for targeted newer agents. Newer agents with unique mechanisms of action may be devoid of drug toxicity, adverse effects, and the ability of parasites to quickly gain resistance, and PfDHODH inhibitors can be those newer agents. Many PfDHODH inhibitors were patented in the past, and the dependency of Plasmodium on de novo pyrimidine provided a new approach for the development of novel antimalarial agents.


Asunto(s)
Antimaláricos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Humanos , Dihidroorotato Deshidrogenasa , Antimaláricos/farmacología , Antimaláricos/química , Plasmodium falciparum/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Patentes como Asunto , Pirimidinas/farmacología , Inhibidores Enzimáticos/farmacología , Nucleótidos de Pirimidina/farmacología
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