4-benzylpiperidine Research Articles

Formononetin derivatives containing benzyl piperidine: A brand new, highly efficient inhibitor targeting Xanthomonas spp

IntroductionPlant bacterial diseases take an incalculable toll on global food security. The indiscriminate use of chemical synthetic pesticide not only facilitates pathogen resistance of pathogenic bacteria, but also poses a major threat to human health and environmental protection. Therefore, it is of great economic value and scientific significance to develop a new antibacterial drug with environmental friendliness and unique mechanism of action. ObjectivesTo design and synthesize formononetin derivatives based on natural products, evaluate their in vitro and in vivo antibacterial activities and elucidate the mechanisms involved. MethodsThe synthesis was carried out by classical active group splicing method. The antibacterial activities were evaluated using turbidimetry and pot experiments. The antibacterial mechanism was further investigated using scanning electron microscopy (SEM), virulence factors, defense enzymes activities, proteomics and metabolomics. Results40 formononetin derivatives containing benzyl piperidine were designed and synthesized. The antibacterial results demonstrated that H32 exhibited the most potent inhibitory effect against Xanthomonas oryzae pv. Oryzae (Xoo) with the EC50 of 0.07 μg/mL, while H6 displayed the highest inhibitory activity against Xanthomonas axonopodis pv. Citri (Xac) with the EC50 of 0.24 μg/mL. Furthermore, the control efficacy of H32 against rice bacterial leaf blight (BLB) and H6 against citrus canker (CC) was validated through pot experiments. SEM, virulence factors and host enzyme activities assay indicated that H32 could not only reduce the virulence of Xoo, but also activate the activities of defense enzymes and improve the disease resistance of host plants. The proteomics and metabolomics analysis demonstrated that H32 could inhibit the synthesis of branched-chain amino acids, make Xoo cells in a starvation state, inhibit its proliferation, weaken its virulence and reduce its colonization and infection of host cells. ConclusionFormononetin derivatives containing benzyl piperidine could be used as potentially effective inhibitors against Xanthomonas spp.

Molecular docking analysis of substituted 2-(1-benzylpiperidin-4-yl)-5-phenoxy-1H-benzo[d] imidazole derivatives as acetylcholinesterase inhibitors for the management of Alzheimer’s disease

The loss of cholinergic neurons in the brain and hippocampus is the hallmark of Alzheimer’s disease (AD). The hydrolyzing enzyme acetylcholinesterase (AChE) has been identified as a potential treatment for AD. One of the most significant scaffolds for AChE binding is benzyl piperidine, which is included in the medication donepezil. Along with benzimidazole, early investigations have also shown to significantly inhibit AChE. This study includes in designing of a hybrid of benzyl piperidine and benzimidazole as AChE inhibitors. The study revealed that B24, A24, and B8 showed the highest blood–brain barrier (BBB) permeability and binding affinities (−11.4 kcal/mol, 11.0 kcal/mol, and 11.1 kcal/mol, respectively). All the chemicals behaved similarly in the binding pocket of AChE. These important interactions between residues include those between Trp86, Tyr341, Ser293, and others. To stop the BBB from penetrating, polar substitutions on more than two locations were also identified. However, compound B24 is an exception. The series’ most potent ligands may be further evaluated biologically

Progress and Development of Carbazole Scaffold Based as Potential Anti- Alzheimer Agents Using MTDL Approach

Abstract: Alzheimer’s is a neurodegenerative disease (NDs) found in old age people with associated most common symptom dementia. MTDLs (Multi-Target Direct Ligand strategy) is based on a combination of two or more bioactive pharmacophores into a single molecule and this phenomenon has received a great attention in the new era of modern drug discovery and emerging as a choice to treat this complex Alzheimer’s disease (AD). In last fifteen years, many research groups designed, and synthesized new carbazole integrated molecules linked with other bioactive pharmacophores like thiazoles, carvedilol, α- naphthylaminopropan-2-ol, tacrine, ferulic acid, piperazine, coumarin, chalcones, stilbene, benzyl piperidine, adamantane, quinoline, phthalocyanines, α-amino phosphonate, thiosemicarbazones, hydrazones, etc. derivatives using MTDLs approach to confront AD. The present review entails the scientific data on carbazole hybrids as potential Anti-Alzheimer activities from 2007 to 2021 that have shown potential anti-Alzheimer activities through multiple target pathways thereby promising hope for new drug development to confront AD.

New 5-Aryl-1,3,4-Thiadiazole-Based Anticancer Agents: Design, Synthesis, In Vitro Biological Evaluation and In Vivo Radioactive Tracing Studies.

A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (3), substituted piperazines (4a-g), benzyl piperidine (4i), and aryl aminothiazoles (5a-e) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds 4e and 4i displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of 4e and 4i towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound 4e or 4i induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either 4e or 4i indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound 4i proved its targeting ability to sarcoma cells in a tumor-bearing mice model.

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus.

Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

New classes of carbazoles as potential multi-functional anti-Alzheimer’s agents

Multi-Target approach is particularly promising way to drug discovery against Alzheimer's disease. In the present study, we synthesized a series of compounds comprising the carbazole backbone linked to the benzyl piperazine, benzyl piperidine, pyridine, quinoline, or isoquinoline moiety through an aliphatic linker and evaluated as cholinesterase inhibitors. The synthesized compounds showed IC50 values of 0.11–36.5 µM and 0.02–98.6 µM against acetyl- and butyrylcholinesterase (AChE and BuChE), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 3s could bind effectively to the peripheral anionic binding site (PAS) and anionic site of the enzyme with mixed-type inhibition. Compound 3s was the most potent compound against AChE and BuChE and showed acceptable inhibition potency for self- and AChE-induced Aβ1-42 aggregation. Moreover, compound 3s could significantly protect PC12 cells against H2O2-induced toxicity. The results suggested that the compounds 3s could be considered as a promising multi-functional agent for further drug discovery development against Alzheimer's disease.

Developing a nontoxic and biocompatible polymeric self-assembly by using RAFT methodology for biomedical application

The amphiphilic block copolymer poly(N-vinylpyrrolidone)-b-poly(N-vinylcarbazole) (PVP-b-PVK) was synthesized by reversible-deactivation radical polymerization (RDRP)using reversible addition-fragmentation chain transfer (RAFT) methodology by new chain transfer agent (CTA) i.e. benzyl piperidine dithiocarbamate (BPDC). The pseudo-first-order kinetics and linear evolution of the molar mass with N-vinylpyrrolidone (NVP) conversion were obtained with the molar mass dispersity (Ð) 1.30–1.41 in toluene. 1H NMR spectrum indicates the presence of chain-end functional groups on homopolymer and block copolymer. The above block copolymer get self-assembled and form micelles in the aqueous medium, the size of micelles is characterized by 1H NMR, transmission electron micrographs (TEM) and dynamic laser light scattering (DLS) analyses, and critical micelles concentration (CMC) was determined by UV–vis spectroscopy. Trypan blue exclusion and MTT assay were done to ensure the cytotoxic effect of PVP-b-PVK on different types of normal cells (thymocytes, splenocytes and macrophage), and no cytotoxic effect was shown by block copolymer on cells, while observed biocompatibility with cells was 200 mg/mL. Further, the beads of block copolymer releases (65%) highly water-soluble levofloxacin drug up to 8 h in a controlled manner at pH 7.4 (37 ± 0.2 °C), while loading of levofloxacin drug was 62% (w/w).

Chameleon-like behavior of indolylpiperidines in complex with cholinesterases targets: Potent butyrylcholinesterase inhibitors

Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and β-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective hBuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE.

A Second Generation Synthesis of Benzyl Piperidine Derivatives: A Key Intermediate for the Preparation of SERT/5-HT1A Dual Inhibitor

A second generation process for benzyl piperidine 10 is described. By the use of a Horner–Wadsworth–Emmons reaction and selective hydrogenation with Pt/C in ethyl acetate, 2-bromo-5-(hydroxymethyl) phenol 14 was efficiently converted to the compound 10 on a 5 kg scale. A small amount of water was found to be critical to complete the selective hydrogenation with low levels of debrominated byproduct 15. Impurities of the compound 10 were controlled by limiting the quality of 2-bromo-5-(hydroxymethyl) phenol 14 and 1-bromo-2-methoxyethane 15.

Adsorption and corrosion inhibitive properties of piperidine derivatives on mild steel in phosphoric acid medium

The present study describes the inhibition effect of 4-benzyl piperidine (P1), 1,6-bis(4-benzylpiperidine-1-carboxamide)hexane (P2) and bis(4-benzylpiperidine)thiuram disulfide (P3) towards the corrosion of mild steel in 5.5 M H3PO4 solution using weight loss measurements and polarization technique. The influence of inhibitor concentration and temperature on the inhibitory behavior of P2 and P3 was investigated. Meanwhile, the inhibition efficiency (IE) was found to depend on the molecule structure and the concentration of piperidine derivatives. The IE for 10−3 M P2 and P2 in 5.5 M H3PO4 is around 90 %. Polarization studies clearly revealed that all the compounds used act as mixed-type inhibitors. Adsorption isotherms were fitted by the Langmuir isotherm. Adsorption energies ( $$ \Updelta {\text{G}}^\circ_{\text{ads}} $$ and $$ \Updelta {\text{H}}^\circ_{\text{ads}} $$ ) and kinetic parameters were evaluated. Significant correlations are obtained between inhibition efficiency with the calculated chemical indexes, indicating that the variation of inhibition with structure of the inhibitor may be explained in terms of electronic properties.

Modeling Anti-HIV Compounds: The Role of Analogue-Based Approaches

There has been a tremendous progress in the development of anti-HIV therapies since the discovery of the HIV virus. Computer aided drug design in general and analogue-based approaches in particular have played an important role in the process of HIV drug discovery. Structure-based approaches also have played a vital role in this process. There are a large number of studies reported in the literature where QSAR methodology was employed to study the structural requirements for inhibition against various HIV targets like reverse transcriptase, protease, entry and integrase. The current review focuses on those studies and provides a detailed description on the QSAR methodology, descriptors, statistical significance and important findings. This review categorizes the reported QSAR studies on the basis of chemical scaffolds against a particular target. In reverse transcriptase category, QSAR studies on HEPT, TIBO, DABO, DAPY, DATA, AASBN, pyridone and DATZD derivatives have been reviewed. Cyclic urea, fullerene, AHPBA and dihydropyrone derivatives were considered in protease inhibitors category. In addition, QSAR studies on styrylquinoline, carboxylic acid, MBSA and chalcone derivatives were reviewed in integrase inhibitors category. QSAR studies on entry inhibitors like piperidine, benzyl piperidine, benzyl pyrazole, pyrrole and diazepane urea have also been reviewed.

Design, synthesis, and pharmacological evaluation of haloperidol derivatives as novel potent calcium channel blockers with vasodilator activity.

Several haloperidol derivatives with a piperidine scaffold that was decorated at the nitrogen atom with different alkyl, benzyl, or substituted benzyl moieties were synthesized at our laboratory to establish a library of compounds with vasodilator activity. Compounds were screened for vasodilatory activity on isolated thoracic aorta rings from rats, and their quantitative structure–activity relationships (QSAR) were examined. Based on the result of QSAR, N-4-tert-butyl benzyl haloperidol chloride (16c) was synthesized and showed the most potent vasodilatory activity of all designed compounds. 16c dose-dependently inhibited the contraction caused by the influx of extracellular Ca2+ in isolated thoracic aorta rings from rats. It concentration-dependently attenuated the calcium channel current and extracellular Ca2+ influx, without affecting the intracellular Ca2+ mobilization, in vascular smooth muscle cells from rats. 16c, possessing the N-4-tert-butyl benzyl piperidine structure, as a novel calcium antagonist, may be effective as a calcium channel blocker in cardiovascular disease.

LXXX.—The nitration of benzylpyridines and the oxidation of benzylpiperidines

LXXX.—The nitration of benzylpyridines and the oxidation of benzylpiperidines