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Graphical abstract Highlights • Novel p-aminobenzoic acid derivatives were designed, synthesized and characterized. • The compounds exhibited significant inhibitory potential against AChE and BChE. • Compound 22 exhibited significant improvements in working and reference memory. • The ex vivo study confirmed the ability of compound 22 to cross the BBB. • The in silico studies demonstrated the binding to active pocket in a stable manner. Abstract Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE. [ABSTRACT FROM AUTHOR]

Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2- a ]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53 – 60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC 50 = 14.91 μM, Ki = 0.72 µM) over COX-1 (IC 50 > 50 μM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC 50 = 13.09 μM, Ki = 0.92 µM). Thus, in silico, in vivo , and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs. [ABSTRACT FROM AUTHOR]

Series of some 3,5-dimethoxy- N -methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N -methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC 50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4 . The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory. [ABSTRACT FROM AUTHOR]

• In-silico based virtual screening of a library (Drug Central Database) containing 4199 FDA approved drugs; MM/GBSA and MD simulation analysis were performed. • Novel structurally modified propamidine derivatives were synthesized, characterized and tested for their anti-AD activity. • Compound 27 was a well-balanced and promising multi-targeting agent. • Compound 27 exhibited good self and AChE-induced Aβ aggregation inhibition in thioflavin T assay. • Compound 27 displayed significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. The use of multifunctional agents could act as a crucial strategy in the management of neurodegenerative disorders like Alzheimer's disease (AD). In search of multitargeted directed ligands for the treatment of AD, a drug repositioning study has been performed using In silico tools. Virtual screening of a library (Drug Central Database) containing 4199 FDA-approved drugs was utilized for the purpose, and denopamine, guanethidine, and propamidine were identified as hits to target both acetylcholinesterase (AChE) and β-secretase (BACE-1). Further, MM/GBSA and MD simulation analysis was also performed which suggested that propamidine, an antibacterial and antifungal drug , may become a crucial pharmacophore to design multi-target directed ligands for AD therapy. Finally, a series of structurally modified derivatives of propamidine by replacement of terminal amidines with substituted benzamide and acetamide moiety on both ends were synthesized, characterized, and tested for their anti-AD action. Compound 27 of the structurally modified series of propamidine has shown significant in vitro hAChE and hBACE-1 inhibition at submicromolar concentration range (hAChE: IC 50 = 0.832 ± 0.05 µM and hBACE-1: IC 50 = 0.428 ± 0.036 µM). Compounds 27 has also shown significant propidium iodide displacement from the PAS binding region and exhibited good self and AChE-induced Amyloid-β (Aβ) aggregation inhibition in thioflavin T assay. The in-vivo behavioral studies of compound 27 displayed significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Some new semicarbazones of 4-aminopyridine were synthesized and evaluated for antiamnesic, cognition enhancing and anticholinesterase activities. The results illustrated a significant cognition enhancing effect on elevated plus maze model with a significant reversal of scopolamine-induced amnesia. A significant inhibition in acetycholinesterase (AChE) activity by all the synthesized compounds in specific brain regions that is, prefrontal cortex, hippocampus and hypothalamus was observed. Compound 4APi exhibited significant antiamnesic and cognition enhancing activity which was comparable with standard drug donepezil. Its enzyme kinetic study revealed a non-competitive inhibition of AChE and a competitive inhibition of butyrylcholinesterase (BChE). Docking studies predicted the binding modes of these compounds in AChE active site, which were further processed for molecular dynamics simulation for calculating binding free energies using Molecular Mechanics–Generalized Born Surface Area (MM/GBSA). All the computational study confirmed their consensual interaction with AChE justifying the experimental outcome. [Copyright &y& Elsevier]

Abstract: Some new anilide and imide derivatives of 4-aminopyridine (4AP) were synthesized and evaluated against antiamnesic, cognition enhancing and anticholinesterase activity through their respective in vitro and in vivo models. These newly synthesized derivatives have illustrated an enhanced cognition effect on elevated plus maze model and also demonstrated a significant reversal in scopolamine-induced amnesia in same model. The IC50 value of synthesized compounds showed maximum activity of 4APMb compared to standard drug donepezil and other derivatives, whereas its enzyme kinetic study revealed a non-competitive inhibition of acetycholinesterase (AChE) and a competetive inhibition of butyrylcholinesterase (BChE). Significant inhibitions in AChE activity by all the synthesized compounds were found in specific brain regions that is prefrontal cortex, hippocampus and hypothalamus. The docking study confirmed their consensual interaction with AChE, showed an affinity and binding with the key peripheral anionic site residues Trp-286, Tyr-124 and Tyr-341 of AChE. [Copyright &y& Elsevier]

In this manuscript we have designed and synthesized 1,4-Naphthoquinone analogs substituted with 1,3,4 Oxadiazolenucleus. The synthesized compound (M1-M14) were characterized using the different analytical technique¹H NMR, 13C NMR, FTIR, Mass spectroscopy, melting point, elemental analysis and further subjected for the evaluation of their anticancer activity using MCF-7, Hela and HepG2 cancer cell lines. The compound M-5 was found to exhibit most potent cytotoxicity against cancer cell lines i.e. HeLa (IC50 =10.76 ± 0.11 µM), MCF-7 (IC50 = 9.30 ± 0.14 µM) and HepG2 (IC50 = 11.93 ± 0.38µM). Compound M-5 has also shown potent tyrosine kinase inhibitory activity with IC50 = 1.53 ± 0.05 µM. Moreover, molecular docking has exposed that compound M-5 has strong binding affinity to the active site of tyrosine kinase. These results give promising beginning stages to assist in the improvement of novel and powerful anticancer agents. [ABSTRACT FROM AUTHOR]

In this manuscript, we have designed, synthesized and characterized 1, 4-naphthoquinone derivatives. The synthesized compounds (MB1-MB19) were further subjected for evaluation of their anticancer activity using MCF-7, HeLa and HepG2 cancer cell lines. The compound MB-9 was observed to be most active against these three cancer cell lines i.e. MCF-7 (IC50 = 15.63 ± 0.47 µM), HeLa (IC50 =13.45 ± 0.48 µM), and HepG2 (IC50 = 23.87 ± 0.59µM). Compound MB-9 has also shown potent tyrosine kinase inhibitory activity with IC50 = 1.80 ± 0.06 µM. Moreover, molecular docking investigations revealed that compound MB-9 has strong binding affinity to the active site residues of tyrosine kinase. These outcomes give a promising beginning to assist in the improvement of novel and powerful anticancer agents. [ABSTRACT FROM AUTHOR]

Epilepsy is the most common chronic neurological disorder of the brain. For several decades different kinds of medications have been used to treat epilepsy. Even though many surgical advances has been made and implemented, medications remain the basis of treatment. The search for noble antiepileptic drugs (AEDs) with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. Additionally, drug resistance is an important clinical problem in epilepsy and is associated with an increased risk of morbidity and mortality. This review intends to present a comprehensive overview on AED in particular along with discussion on some aspects of associated drug resistance and combination therapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Novel hybrids bearing a 2-aminopyrimidine (2-AP) moiety linked to substituted 1,3,4-oxadiazoles were designed, synthesized and biologically evaluated. Among the developed compounds, 28 noncompetitively inhibited human acetylcholinesterase (hAChE; pIC 50 = 6.52; Ki = 0.17 µM) and showed potential in vitro antioxidant activity (60.0%) when evaluated using the Ellman's and DPPH assays, respectively. Compound 28 competitively displaced propidium iodide (PI) from the peripheral anionic site (PAS) of hAChE (17.6%) and showed high blood-brain barrier (BBB) permeability, as observed in the PAMPA-BBB assay. Additionally, compound 28 inhibited hAChE-induced Aβ aggregation in a concentration-dependent manner according to the thioflavin T assay and was devoid of neurotoxic liability towards SH-SY5Y cell lines, as demonstrated by the MTT assay. The behavioral studies of compound 28 in mice showed a significant reversal of scopolamine-induced amnesia, as observed in Y-maze and passive avoidance tests. Furthermore, compound 28 exhibited significant AChE inhibition in the brain in ex vivo studies. An evaluation of oxidative stress biomarkers revealed the antioxidant potential of 28. Moreover, in silico molecular docking and dynamics simulation studies were used as a computational tool to evaluate the interactions of compound 28 with the active site residues of hAChE. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Biphenyl-3-oxo-1,2,4-triazine linked piperazines were designed and synthesized. • Compound 6g significantly inhibited the AChE and showed good CNS permeability. • In vivo studies showed significant improvement in learning and memory. • Biochemical analysis showed potential antioxidant property by compound 6g. Abstract A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC 50 ; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC 50 : 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (P e (exp) , 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE. [ABSTRACT FROM AUTHOR]

Some promising acetylcholinesterase (AChE) inhibitors with an antioxidant potential were designed, synthesised, and evaluated for their role in treating cognitive dysfunctions. The in silico Gaussian-based quantitative structureactivity relationship (QSAR), virtual screening (VS), QikProp drug-likeliness prediction and docking pose filtration protocols were adapted to design and screen the novel series of diaryl ether derivatives. Further, the selected compounds were investigated for their molecular binding stability using molecular dynamics (MD) simulation analysis and molecular mechanics generalised born surface area (MM-GBSA). The identified hits were synthesised and evaluated for their in vitro AChE inhibition and antioxidant potential. Among all the synthesized compounds, the compound 39 was observed as potent AChE inhibitor (AChE IC50 = 1.30 ± 0.09 μm; Ki = 0.054 ± 0.009 μM), and also the antioxidant potential of compound 39 (52.9%) was observed significantly better than standard donepezil (<10%) and parallel to ascorbic acid (56.6%). Further, compound 39 ameliorated the scopolamine-induced cognitive impairment in the Y-maze and passive avoidance testsin mice models. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of compound 39. The results signified compound 39 to be a promising lead for the treatment of cognitive dysfunctions. [ABSTRACT FROM AUTHOR]

Highlights • The pathophysiological roles and underlying mechanisms of several hypotheses involved in AD are extensively reviewed. • A detailed investigation of all the conventional and novel therapeutic targets. • The identification of structural and functional motifs with a comprehensive framework of the active sites involved. • To elucidate and simplify the complexity and call for attention on the crucial areas to discover innovative therapeutics. Abstract AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aβ, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] Alzheimer's disease (AD) is a progressive neurological illness that causes dementia mainly in the elderly. The challenging obstacles related to AD has freaked global healthcare system to encourage scientists in developing novel therapeutic startegies to overcome with the fatal disease. The current treatment therapy of AD provides only symptomatic relief and to some extent disease-modifying effects. The current approach for AD treatment involves designing of cholinergic inhibitors, Aβ disaggregation inducing agents, tau inhibitors and several antioxidants. Hence, extensive research on AD therapy urgently requires a deep understanding of its pathophysiology and exploration of various chemical scaffolds to design and develop a potential drug candidate for the treatment. Various issues linked between disease and therapy need to be considered such as BBB penetration capability, clinical failure and multifaceted pathophisiology requires a proper attention to develop a lead candidate. This review article covers all probable mechanisms including one of the recent areas for investigation i.e., lipid dyshomeostasis, pathogenic involvement of P. gingivalis and neurovascular dysfunction, recently reported molecules and drugs under clinical investigations and approved by FDA for AD treatment. Our summarized information on AD will attract the researchers to understand and explore current status and structural modifications of the recently reported heterocyclic derivatives in drug development for AD therapy. [ABSTRACT FROM AUTHOR]

Analgesic drugs containing free acidic group were reacted with N, N' carbonyldiimidazole to prepare the acylimidazole derivatives. They were further reacted with 5-phenyl-2-amino thiazole nucleus to obtain the corresponding amides. All the compounds were found to retain analgesic-antiinflammatory activities with much lesser NSAID-induced GI complications when compared with the standard. [ABSTRACT FROM AUTHOR]