Synthesis, characterization, and in silico studies of 1,8-naphthyridine derivatives as potential anti-Parkinson's agents.

1,8-Naphthyridine scaffold is a nitrogen-containing heterocyclic compound known for its versatile biological activities. The structure-activity relationship (SAR) has shown that modification at the 3rd position of the nucleus with various secondary amines enhances the binding efficiency and potency towards the Adenosine receptor (A2A type). In this paper, we have reported some newly synthesized derivatives of 1,8- Naphthyridine, and the prepared compounds were assessed for their potential to constrain A2A receptors through molecular docking. Based on the SAR studies, modifications were done at the 3rd position of the nucleus by incorporating secondary amines. The synthesized compounds were characterized by FT-IR, 1H and 13C NMR. All the synthesized compounds 10a-f and 13a-e showed good binding efficiency towards the A2A receptors and might act as an A2A receptor antagonist, as predicted by in-silico studies. 1-Ethyl-7-methyl-3-(pyrrolidine-1-carbonyl)-1,8-naphthyridine-4(1H)-one (10c) in first series showed the highest docking score of -8.407 and binding energy (MMGBSA dG bind) of -56.60 kcal/mol and N-(4-2-diethylaminoethoxyphenyl)-1-ethyl-7-methyl-4-oxo-1, 4, 4a, 8a- tetrahydro-1,8-naphthyridine-3-carboxamide (13b) showed the highest docking score of -8.562 and free binding energy (MMGBSA dG bind) score of -64.13 kcal/mol which was comparable to the bound ligand. MD simulations study also suggested that compounds 10c and 13b would form stable complex human A2A receptor. These findings need to be validated by further in vitro assays.Communicated by Ramaswamy H. Sarma.

A Recent Appraisal of Small-Organic Molecules as Anti-Alzheimer's Agents.

BACKGROUND: Alzheimer's disease (AD) is an irreversible, progressive and very complex brain disorder. There is still uncertainty about the etiology of AD; however, a few hallmarks like an aggregation of tau proteins, amyloid-ß plaques, oxidative stress, low level of choline in the brain etc., play significant roles. OBJECTIVE: In the present work, we aim to evaluate the recent progress in the development of small organic molecules containing heterocycles like thiazole, pyridines, dihydropyridines, piperidines, pyrrolidines, pyrazoles, quinolines etc. as anti-Alzheimer's agents. METHODS: Several databases, including SciFinder, ScienceDirect, Bentham Science, and PubMed, were searched for relevant articles and reviewed for the present work. RESULTS: Several research groups are actively working on these heterocycle-based compounds as potent single-target inhibitors. Most of the analogues have been evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition potential. Several studies have also reported the inhibitory potential of the analogues against MAO-A, MAO-B, and BACE-1 enzymes. However, instead of targeting one enzyme or protein, more than one heterocycle ring is being joined to develop MTDLs (multi-target-directed ligands). Donepezil has become the focal point of anti-AD drug discovery projects. Several research groups have reported various donepezil-based analogues by replacing/ modifying its various ring systems like indanone, piperidine or the methylene linker. CONCLUSION: Small molecules with nitrogen-containing heterocycles have become the core of drug discovery efforts for AD. With the increasing prominence of the MTDL approach, several new ligands are being discovered as potent anti-AD agents.

1,8-Naphthyridine Derivatives: A Privileged Scaffold for Versatile Biological Activities.

1, 8- Naphthyridine nucleus belongs to significant nitrogen-containing heterocyclic compounds which has garnered the interest of researchers due to its versatile biological activities. It is known to be used as an antimicrobial, anti-psychotic, anti-depressant, anti-convulsant, anti- Alzheimer's, anti-cancer, analgesic, anti-inflammatory, antioxidant, anti-viral, anti-hypertensive, antimalarial, pesticides, anti-platelets, and CB2 receptor agonist, etc. The present review highlights the framework of biological properties of synthesized 1, 8-naphthyridine derivatives developed by various research groups across the globe.

Bronchospasmolytic and Adenosine Binding Activity of 8- (Proline / Pyrazole)- Substituted Xanthine Derivatives.

BACKGROUND: 8-Phenyltheophylline derivatives exhibit prophylactic effects at a specific dose but do not produce the cardiovascular or emetic side effects associated with xanthines, thereby exhibiting unique characteristics of potential therapeutic importance. METHODS: Novel series of 8-(proline/pyrazole)-substituted xanthine analogs have been synthesized. The affinity and selectivity of compounds to adenosine receptors have been assessed by radioligand binding studies. The synthesized compounds also showed good bronchospasmolytic properties (increased onset of bronchospasm; decreased duration of jerks) with 100% survival of animals in comparison to the standard drug. Besides, compound 8f & 9f showed good binding affinity in comparison to other synthesized compounds in the micromolar range. RESULTS: The maximum binding affinity of these compounds was observed for A2B receptors, which was ~ 7 or 10 times higher as compared to A1, A2A and A3 receptors. The newly synthesized derivatives 8f, 9a-f, 17g-m, and 18g-m displayed significant protection against histamine aerosol induced bronchospasm in guinea pigs. CONCLUSION: Newly synthesized proline/pyrazole based xanthines compounds showed a satisfactory binding affinity for adenosine receptor subtypes. Replacement or variation of substituted proline ring with substituted pyrazole scaffold at the 8th-position of xanthine moiety resulted in the reduction of adenosine binding affinity and bronchospasmolytic effects.

Novel Benzylated (Pyrrolidin-2-one)/(Imidazolidin-2-one) Derivatives as Potential Anti-Alzheimer's Agents: Synthesis and Pharmacological Investigations.

A series of N-benzylated (pyrrolidin-2-one)/(imidazolidin-2-one) derivatives were synthesized and evaluated for anti-Alzheimer's activity. The analogs were designed and synthesized on the basis of lead compound donepezil, which is currently prescribed as a major drug for the management of mild to severe Alzheimer's disease. Considering the structure activity relationship (SAR) of the lead compound, we first replaced the 5,6-dimethoxy-1-indanone moiety with N-benzylated (pyrrolidin-2-one)/(imidazolidin-2-one) (head) without depriving the key functionality interactions like carbonyl and dimethoxyphenyl and second substituted the spacer linkage (tail) in donepezil. The newly synthesized compounds were characterized by structural conformity and purity using various techniques. The compounds were then subjected to in vivo (behavioral studies) and in vitro (biochemical assays) evaluation using appropriate animal models against the standard drug. Compounds 3-(4-(4-fluorobenzoyl)-piperidin-1-yl)-1-(4-methoxybenzyl)-pyrrolidin-2-one (10b) and 1-(3,4-dimethoxybenzyl)-3-((1-(2-(trifluoromethyl)-benzyl)-piperidin-4-yl)-methyl)-imidazolidin-2-one (18c) displayed an excellent anti-Alzheimer's profile, while the rest of the compounds showed satisfactory results in comparison to donepezil.