Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors.

A small series of nitro group-bearing enamides was designed, synthesized (NEA1-NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and ß-site amyloid precursor protein cleaving enzyme 1 (ß-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood-brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.

Synthesis, Cytotoxicity and Anti-Proliferative Activity Against AGS Cells of New 3(2H)-Pyridazinone Derivatives Endowed with a Piperazinyl Linker.

Novel twenty-three 3(2H)-pyridazinone derivatives were designed and synthesized based on the chemical requirements related to the anti-proliferative effects previously demonstrated within this scaffold. The introduction of a piperazinyl linker between the pyridazinone nucleus and the additional (un)substituted phenyl group led to some compounds endowed with a limited cytotoxicity against human gingival fibroblasts (HGFs) and good anti-proliferative effects against gastric adenocarcinoma cells (AGS) as evaluated by MTT and LDH assays, using doxorubicin as a positive control. Successive analyses revealed that the two most promising representative compounds (12 and 22) could exert their effects by inducing oxidative stress as demonstrated by the hydrogen peroxide release and the morphological changes (cell blebbing) revealed by light microscopy analysis after the haematoxylin-eosin staining. Moreover, to further assess the apoptotic process induced by compounds 12 and 22, Bax expression was measured by flow cytometry. These findings enlarged our knowledge of the structural requirements in this scaffold to display valuable biological effects against cancerous cell lines.

Advancements in nanotherapeutics for Alzheimer's disease: current perspectives.

Objectives Considerable progress has been made in the treatment of Alzheimer's disease (AD), but all available strategies focus on alleviating symptoms rather than curing, which means that AD is viewed as an unresolvable neurodegenerative disease. Nanotechnological applications offer an alternative platform for the treatment of neurodegenerative diseases. This review aims to summarize the recent nanomedicine and nanotechnology developments for the treatment of AD.  Key findings A plethora of nanocarriers and nanoparticle prodrugs have been reported to have negligible cytotoxicity in animal models, and these developments have revealed new opportunities for development of new classes of potent drug formulations for AD. Different nanotechnology-based approaches such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes and metal-based carriers have been developed over the past decade, and they have been focusing on both neuroprotective and neurogenerative techniques to treat AD. Studies also reveal that nanotechnological approaches can aid in early diagnosis of AD and enhance therapeutic efficacy and bioavailability.  Summary  Notably, the drugs used conventionally to target the central nervous system have limitations that include an inability to cross the 'blood-brain barrier' or the 'blood-cerebrospinal fluid barrier' effectively and high drug efflux due to the activity of P-glycoprotein, but these limitations can be successfully overcome when nanocarriers are used for targeted drug delivery in AD.

Aptamers in Drug Design: An Emerging Weapon to Fight a Losing Battle.

Implementation of novel and biocompatible polymers in drug design is an emerging and rapidly growing area of research. Even though we have a large number of polymer materials for various applications, the biocompatibility of these materials remains as a herculean task for researchers. Aptamers provide a vital and efficient solution to this problem. They are usually small (ranging from 20 to 60 nucleotides, single-stranded DNA or RNA oligonucleotides which are capable of binding to molecules possessing high affinity and other properties like specificity. This review focuses on different aspects of Aptamers in drug discovery, starting from its preparation methods and covering the recent scenario reported in the literature regarding their use in drug discovery. We address the limitations of Aptamers and provide valuable insights into their future potential in the areas regarding drug discovery research. Finally, we explained the major role of Aptamers like medical imaging techniques, application as synthetic antibodies, and the most recent application, which is in combination with nanomedicines.