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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]

Novel Schiff bases of 1-(2-Aminoethyl)piperidine-3-carboxylic acid were synthesized, characterized and screened for anticonvulsant activity. Compounds were evaluated for in vitro blood-brain barrier (BBB) permeability by parallel artificial membrane permeability BBB assay (PAMPA-BBB). Compounds 5d, 5f, 5j, 5l, 5m, 5n, 5w, 5x and 5y elicited considerable in vitro permeability across BBB and further screened for in vivo anticonvulsant activity by sc-PTZ and DMCM-induced seizure models. The outcome of the in vivo models suggested that 5d, 5w, and 5y were most potent amongst the synthesized compounds. The neurotoxicity evaluation of 5d, 5w, and 5y by rotarod indicates no impairment of muscle coordination in comparison to standard diazepam. The MTT assay revealed that the test compounds (5d, 5w, and 5y) were not found to alter the cell viability considerably. In silico molecular docking and dynamics simulations were carried out on the homology modeled protein of human GABA transporter 1 (GAT1), which exhibited complementary interactions of compound 5w within the active binding pocket. [ABSTRACT FROM AUTHOR]

Abstract: The objective of work was to formulate, evaluate and compare the transdermal potential of novel vesicular nanocarriers: ethosomes and ultradeformable liposomes, containing clotrimazole (CLT), an anti-fungal bioactive. The ethosomal formulation (ET4) and ultradeformable liposomal (UL) formulation (TT3) showed highest entrapment 68.73±1.4% and 55.51±1.7%, optimal nanometric size range 132±9.5nm and 121±9.7nm, and smallest polydispersity index 0.027±0.011 and 0.067±0.009, respectively. The formulation ET4 provided enhanced transdermal flux 56.25±5.49μg/cm2/h and decreased the lag time of 0.9h in comparison to TT3 formulation (50.16±3.84μg/cm2/h; 1.0h). Skin interaction and FT-IR studies revealed greater penetration enhancing effect of ET4 than TT3 formulation. ET4 formulation also had the highest zone of inhibition (34.6±0.57mm), in contrast to TT3 formulation (29.6±0.57mm) and marketed cream formulation (19.0±1.00mm) against candidal species. Results suggested ethosomes to be the most proficient carrier system for dermal and transdermal delivery of clotrimazole. [Copyright &y& Elsevier]

• 4-AP tethered 1,3,4-oxadiazole derivatives were designed and synthesized. • Compound 9 elicited significant non-competitive type of hAChE inhibition. • Compound 9 showed significant brain permeability in PAMPA-BBB assay. • Compound 9 ameliorated scopolamine- induced cognitive impairment in mice models. • Biochemical analysis using brain homogenates suggested antioxidant activity by 9. The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC 50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC 50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aβ aggregation (38.2–65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates. [ABSTRACT FROM AUTHOR]

Novel hybrids N-(4-phenoxybenzyl)aniline were designed, synthesized, and evaluated for their potential AChE inhibitory activity along with antioxidant potential. The inhibitory potential (IC 50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the tested compounds, 42 with trimethoxybenzene substituent showed maximum hAChE inhibition with the competitive type of enzyme inhibition (IC 50 = 1.32 µM; Ki = 0.879 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed favorable BBB permeability by most of the synthesized compounds. Meanwhile, compound 42 also inhibited AChE-induced Aβ aggregation (39.5–66.9%) in thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 42. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 42 in brain homogenates. [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]

• Design and synthesis of N -benzylpyrrolidine analogs. • Compounds 4k and 4o exhibited balanced inhibition of AChE, BChE, and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 4k and 4o. • Ex vivo study of rat hippocampal homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. Multitarget molecular hybrids of N -benzyl pyrrolidine derivatives were designed, synthesized, and biologically evaluated for the treatment of Alzheimer's disease (AD). Among the synthesized compounds, 4k and 4o showed balanced enzyme inhibitions against cholinesterases (AChE and BChE) and BACE-1. Both leads showed considerable PAS-AChE binding capability, excellent brain permeation, potential disassembly of Aβ aggregates, and neuroprotective activity against Aβ-induced stress. Compounds 4k and 4o also ameliorated cognitive dysfunction against the scopolamine-induced amnesia model in the Y-maze test. The ex vivo study signified attenuated brain AChE activity and antioxidant potential of compounds 4k and 4o. Furthermore, compound 4o also showed improvement in Aβ-induced cognitive dysfunction by the Morris water maze test with excellent oral absorption characteristics ascertained by the pharmacokinetic study. In silico molecular docking and dynamics simulation studies of leads suggested their consensual binding affinity toward PAS-AChE in addition to aspartate dyad of BACE-1. [ABSTRACT FROM AUTHOR]

• Design and synthesis of ferulic acid-based 1,3,4-oxadiazole hybrids. • Compounds 6j and 6k exhibited balanced inhibition of AChE, BChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 6j and 6k. • Ex vivo study of rat hippocampal homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. Thirty ferulic acid-based 1,3,4-oxadiazole molecular hybrids were designed, synthesized, and screened them for multifunctional inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-secretase-1 (BACE-1). Compound 6j was the most potent inhibitor of AChE (IC 50 = 0.068 µM). It also showed equipotent inhibition of BChE and BACE-1 with IC 50 values of 0.218 µM and 0.255 µM, respectively. Compound 6k possessed the most significant inhibition of BChE and BACE-1 with IC 50 values, 0.163 µM and 0.211 µM, respectively. Compounds 6j and 6k elicited significant displacement of propidium iodide from PAS-AChE, excellent BBB permeability in PAMPA assay, and anti-Aβ aggregatory activity in self- and AChE-induced experiments with neuroprotective activity towards neuroblastoma SH-SY5Y cells. The in vivo behavioral studies suggested amelioration of cognitive dysfunction by 6j and 6k in the Y maze test. The ex vivo study signified brain AChE inhibition and antioxidant activity from these compounds. Moreover, 6j showed improvement in learning and memory behavior in the Aβ-induced ICV rat model by Morris water maze test with excellent oral absorption characteristics ascertained by pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

Ferulic acid-based multifunctional molecular hybrids of 1,3,4-oxadiazoles were designed, synthesized, and biologically evaluated for the treatment of Alzheimer's disease. Among the synthesized compounds, the derivatives with 4- hydroxy-3,5-dimethoxy substituent (FA5 and CFA5) showed balanced inhibitory potential against hAChE, hBChE, and hBACE-1. Also, CFA5displayed remarkable PAS-AChE binding with significant displacement of propidium iodide, and appreciable blood-brain barrier permeability predictions in PAMPA-BBB assay. The thioflavin T assay in self- and AChE-induced experiments established the considerable anti-Aâ aggregatory activity of CFA5. Compound CFA5 also showed neuroprotective activity in Aâ-induced oxidative stress against SH-SY5Y neuroblastoma cell lines. Moreover, in vivo behavioral studies showed amelioration of cognitive dysfunction in rats tested by Y-maze. In silico molecular docking study showed consensual binding interactions of CFA5 with active binding site residues of AChE and BACE-1. [ABSTRACT FROM AUTHOR]

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]

A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2 H )-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c – 3e and 4c–4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c – 3e and 4c–4e (IC 50 0.60–1.11 μM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an enormous healthcare challenge, and 50 million people are currently suffering from it. There are several pathophysiological mechanisms involved, but cholinesterase inhibitors remained the major target from the last 2-3 decades. Among four available therapeutics (donepezil, rivastigmine, galantamine, and memantine), three of them are cholinesterase inhibitors. Herein, we describe the role of acetylcholine sterase (AChE) and related hypothesis in AD along with the pharmacological and chemical aspects of the available cholinesterase inhibitors. This chapter discusses the development of several congeners and hybrids of available cholinesterase inhibitors along with their binding patterns in enzyme active sites.

Background: Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial γ-aminobutyric acid (GABA) uptake in vitro. However, nipecotic acid does not readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its hydrophilic nature., Objective: A series of substituted acetonaphthones tethered nipecotic acid derivatives were designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier (BBB) permeation., Methods: Synthesized compounds were tested in mice models of PTZ, pilocarpine, and DMCM induced epilepsy, in vivo. The rota-rod test was performed to determine the acute neurotoxicity of the potential leads (4a, 4b, and 4i). These potential hybrids were also evaluated for their ability to cross the BBB by an in vitro parallel artificial membrane permeability BBB assay (PAMPA-BBB). The leads were subjected to in silico molecular docking and dynamics studies on homology modelled protein of human GABA (γ-amino butyric acid) transporter 1 (GAT1) and prediction of their pharmacokinetic properties., Result: Amongst the synthesized derivatives, compounds 3a, 3b, 3i, 4a, 4b, and 4i exhibited increased latency of seizures against subcutaneous pentylenetetrazole (scPTZ) induced seizures in mice. Derivatives 4a, 4b, 4i were more effective compared to nipecotic acid ester counterparts 3a, 3b and 3i placing the importance of the presence of free carboxyl group in the centre. The findings revealed that 4i was comparatively more permeable (Pe= 8.89) across BBB than the standard tiagabine (Pe= 7.86). In silico studies proved the consensual interactions of compound 4i with the active binding pocket., Conclusion: Some nipecotic acid-acetonaphthone hybrids with considerable anti-epileptic activity, drug like properties and the ability to permeate the BBB have been successfully synthesized., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Nifedipine is a potential therapeutic agent for the treatment of cardiovascular disturbances, although it suffers from short half-life (t1/2, 2 hr)., Objective: To address the problem, we first prepared nifedipine loaded sustained release microsponges and then formulated tablets for effective clinical application and patient compliance., Method: Preparations of microsponges were carried out using different compositions of nifedipine and polymer (1:1, 1:2 and 1:3 % molar ratio) using emulsion solvent diffusion technique., Results: The microsponges with molar ratio 1:3 (formulation code: MF-3) found optimized as revealed by analyzing surface morphology, better powder flow properties (angle of repose; 28.80 ± 0.9, Hausner ratio 1.15 ± 0.2, % compressibility 15.28 ± 0.5% and higher % drug content (80 ± 1.9 %). Different batches of tablets were then formulated incorporating MF-3 microsponges and different proportions (10-50 %) of microcrystalline cellulose and starch as additives. Among tablet formulations, batch composed of 48% of MF-3, 30% of MCC, 20 % of starch and 2 % of talc (TF-33), showed 92.73 ± 2.19 % drug release during 24 hr in vitro release study in comparison to other batches including commercial formulation which was found to be released completely in 20 hr. Further, stability analysis revealed good drug retention of loaded nifedipine as well as consistent in vitro release pattern over a period of 90 days at 40°C and 75% RH., Conclusion: The microsponge tablet delivery system was found to be superior concerning the therapeutic advantage as well as manufacturing feasibility of nifedipine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The increasing prevalence and complexity of cardiovascular diseases demand innovative strategies for diagnostic and therapeutic applications to improve patient care/prognoses. Additionally, various factors constrain present cardiovascular therapies, including low aqueous drug solubility, early metabolism, short half-life and drug delivery limitations. The efficient treatment of cardiovascular diseases requires improvement of traditional drug delivery systems. This can be accomplished by using novel nanomaterial that can incorporate diverse bio-actives along with diagnostic agents in a single carrier, referred to as theranostics. This review discusses the state of the art in the applications to diagnosis and therapy of innovative, nanomaterial- based strategies such as lipid based carriers, nanocapsules, magnetic nanoparticles, gold nanoparticles, protein conjugated nanoparticles, dendrimers and carbon-based nanoformulations with a special emphasis on how they can contribute to improving the management of cardiovascular disease.

siRNA technology presents a helpful means of gene silencing in mammalian cells. Advancement in the field includes enhanced attentiveness in the characterization of target and off-target effects employing suitable controls and gene expression microarrays. These will permit expansion in the measurement of single and multiple target combinations and also permit comprehensive efforts to understand mammalian cell processes. Another fact is that the delivery of siRNA requires the creation of a nanoparticulate vector with controlled structural geometry and surface modalities inside the targeted cells. On the other hand, dendrimers represent the class of carrier system where massive control over size, shape and physicochemical properties makes this delivery vector exceptional and favorable in genetic transfection applications. The siRNA therapeutics may be incorporated inside the geometry of the density controlled dendrimers with the option of engineering the structure to the specific needs of the genetic material and its indication. The existing reports on the siRNA carrying and deliverance potential of dendrimers clearly suggest the significance of this novel class of polymeric architecture and certainly elevate the futuristic use of this highly branched vector as genetic material delivery system.

Cardiovascular diseases (CVDs), primarily myocardial infarction (MI), atherosclerosis, hypertension and congestive heart failure symbolize the foremost cause of death in almost all parts of the world. Besides the traditional therapeutic approaches for the management of CVDs, newer innovative strategies are also emerging on the horizon. Recently, gene silencing via small interfering RNA (siRNA) is one of the hot topics amongst various strategies involved in the management of CVDs. The siRNA mechanism involves natural catalytic processes to silence pathological genes that are overexpressed in a particular disease. Also the versatility of gene expression by siRNA deciphers a prospective tactic to down-regulate diseases associated gene, protein or receptor existing on a specific disease target. This article reviews the application of siRNA against CVDs with special emphasis on gene targets in combination with delivery systems such as cationic hydrogels, polyplexes, peptides, liposomes and dendrimers.