ABSTRACT
Despite the applicability of histone deacetylase inhibitors (HDACis) for cancer treatment, several works in the literature have shown that these inhibitors can be used in several other diseases, such as neurodegenerative diseases (NDs). This review begins by discussing the signaling pathways of HDACs, focused on the context of NDs, presenting a discussion about the pharmacophoric features of HDACis and crystal structure analysis and discussing interesting case studies from the literature about the development of HDACis. Additionally, a discussion about the consequences of isoform-selective inhibition vs pan-HDACis on neurotoxic effects and clinical trial investigations of HDACis for NDs is also presented. Finally, we describe our perspective related to the future use of these inhibitors in the pharmacotherapy of NDs.
Subject(s)
Histone Deacetylases , Neurodegenerative Diseases , Histone Deacetylase Inhibitors/therapeutic use , Humans , Neurodegenerative Diseases/drug therapyABSTRACT
Targeting histone deacetylases (HDACs) and phosphatidylinositol 3-kinases (PI3Ks) is a very promising approach for cancer treatment. This manuscript describes the design, synthesis, inâ vitro pharmacological profile, and molecular modeling of a novel class of N-acylhydrazone (NAH) derivatives that act as HDAC6/8 and PI3Kα dual inhibitors. The surprising selectivity for PI3Kα may be related to differences in the conformation in the active site. Cellular studies showed that these compounds act in HDAC6 inhibition and the PI3/K/AKT/mTOR pathway. The compounds that are selective for inhibition of HDAC6/8 and inhibit PI3Kα show potential for the treatment of cancer.
Subject(s)
Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydrazones/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Repressor Proteins/antagonists & inhibitors , Drug Design , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/metabolism , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Models, Molecular , Molecular Structure , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors/chemistry , Repressor Proteins/metabolism , Tumor Cells, CulturedABSTRACT
4-Oxoquinoline derivatives constitute an important family of biologically important substances, associated with different bioactivities, which can be synthesized by different synthetic methods, allowing the design and preparation of libraries of substances with specific structural variations capable of modulating their pharmacological action. Over the last years, these substances have been extensively explored by the scientific community in efforts to develop new biologically active agents, with greater efficiency for the treatment of a variety of diseases. Viral infections have been one of the targets of these studies, although to a lesser extent than other diseases such as cancer and bacterial infections. Nevertheless, the literature provides examples that corroborate with the fact that these substances may act on different pharmacological targets in different viral pathogens. This review provides a compilation of some of the major studies published in recent years showing the discovery and/or development of new antiviral oxoquinoline agents, highlighting, whenever possible, their mechanisms of action.
Subject(s)
4-Quinolones/pharmacology , Antiviral Agents/pharmacology , Virus Diseases/drug therapy , Viruses/drug effects , 4-Quinolones/chemical synthesis , 4-Quinolones/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Drug Development , Humans , Molecular StructureABSTRACT
Duvelisib (Copiktra®) is a dual inhibitor of phosphoinositide 3-kinases (PI3Kδ and PI3Kγ). In 2018, duvelisib was first approved by the Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL)/ small lymphocytic lymphoma (SLL) after at least two prior therapies. Duvelisib has also been approved under accelerated track for relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. In this review, we provide a series of information about duvelisib, such as the development of clinical trials for LLC/SLL and FL and the steps used for its synthesis.
ABSTRACT
Protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. It has been shown that lysine residues play a key role in the formation of these aggregates. Thus, the ability to disrupt aggregate formation by covalently modifying lysine residues could lead to the discovery of therapeutically relevant antiamyloidogenesis compounds. Herein, we demonstrate that an ortho-iminoquinone (IQ) can be utilized to inhibit amyloid aggregation. Using alpha-synuclein and Aß1-40 as model amyloidogenic proteins, we observed that IQ was able to react with lysine residues and reduce amyloid aggregation. We also observed that IQ reacted with free amines within the amyloid fibrils preventing their dissociation and seeding capacity.
Subject(s)
Amyloid beta-Peptides/metabolism , Neuroprotective Agents/pharmacology , Peptide Fragments/metabolism , Protein Aggregation, Pathological/drug therapy , Quinones/pharmacology , alpha-Synuclein/metabolism , Animals , Catechin/analogs & derivatives , Catechin/pharmacology , Catechin/toxicity , Cell Survival/drug effects , Cells, Cultured , Chickens , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , HEK293 Cells , Humans , Lysine/metabolism , Methionine/metabolism , Mice , Micrococcus luteus , Microtubule-Associated Proteins/metabolism , Muramidase/metabolism , Neuroprotective Agents/toxicity , Oxidation-Reduction , Protein Aggregation, Pathological/metabolism , Quinones/toxicity , Tyrosine 3-Monooxygenase/metabolismABSTRACT
We described the synthesis of a new congener series of 1,2,3-triazolyl-4-oxoquinolines and evaluated their ability to inhibit oseltamivir (OST)-resistant influenza strains. Oxoquinoline derivative 1i was the most potent compound within this series, inhibiting 94% of wild-type (WT) influenza neuraminidase (NA) activity. Compound 1i inhibited influenza virus replication with an EC50 of 0.2µM with less cytotoxicity than OST, and also inhibited different OST-resistant NAs. These results suggest that 1,2,3-triazolyl-4-oxoquinolines represent promising lead molecules for further anti-influenza drug design.
