The hybrid compounds as multi-target ligands for the treatment of Alzheimer's Disease: Considerations on Donepezil

: The strategies to combat Alzheimer’s Disease (AD) have been changing with respect to the failures of many drug candidates assessed in clinical studies, the complex pathophysiology of AD, and the limitations of the current drugs employed. So far, none of the targets, either validated or nonvalidated, have been shown to be purely causative in the generation and development of AD. Considering the progressive and the neurodegenerative characteristics of the disease, the main strategy has been based on the design of molecules capable of showing activity on more than one receptor, and it is defined as multi-target ligand design strategy. The hybrid molecule concept is an outcome of this approach. Donepezil, as one of the currently employed drugs for AD therapy, has also been utilized in hybrid drug design studies. This review has aimed to present the promising donepezil-like hybrid molecules introduced in the recent period. Particularly, multi-target ligands with additional activities concomitant to cholinesterase inhibition are preferred.

Synthesis and Structure of the Bis- and Tris-Polyhedral Hybrid Carboranoclathrochelates with Functionalizing Biorelevant Substituents—The Derivatives of Propargylamine Iron(II) Clathrochelates with Terminal Triple C≡C Bond(s)

A synthetic strategy for obtaining structurally flexible hybrid iron(II) carboranoclatrochelates functionalized with biorelevant groups, based on a combination of a 1,3-dipolar cycloaddition reaction with nucleophilic substitution of an appropriate chloroclathrochelate precursor, was developed. In its first stage, a stepwise substitution of the dichloroclathrochelate precursor with amine N-nucleophiles of different natures in various solvents was performed. One of its two chlorine atoms with morpholine or diethylamine in dichloromethane gave reactive monohalogenoclathrochelate complexes functionalized with abiorelevant substituents. Further nucleophilic substitution of their remaining chlorine atoms with propargylamine in DMF led to morpholine- and diethylamine-functionalized monopropargylamine cage complexes, the molecules of which contain the single terminal C≡C bond. Their “click” 1,3-cycloaddition reactions in toluene with ortho-carborane-(1)-methylazide catalyzed by copper(II) acetate gave spacer-containing di- and tritopic iron(II) carboranoclatrochelates formed by a covalent linking between their different polyhedral(cage) fragments. The obtained complexes were characterized using elemental analysis, MALDI-TOF mass, UV-Vis, 1H, 1H{11B}, 11B, 11B{1H}, 19F{1H} and 13C{1H}-NMR spectra, and by a single crystal synchrotron X-ray diffraction experiment for the diethylamine-functionalized iron(II) carboranoclathrochelate. Its encapsulated iron(II) ion is situated almost in the center of the FeN6-coordination polyhedron possessing a geometry intermediate between a trigonal prism and a trigonal antiprism with a distortion angle φ of approximately 28º. Conformation of this hybrid molecule is strongly affected by its intramolecular dihydrogen bonding: a flexibility of the carborane-terminated ribbed substituent allowed the formation of numerous C–H…H–B intramolecular interactions. The H(C) atom of this carborane core also forms the intermolecular C–H…F–B interaction with an adjacent carboranoclathrochelate molecule. The N–H…N intermolecular interaction between the diethylamine group of one hybrid molecule and the heterocyclic five-membered 1Н-[1,2,3]-triazolyl fragment of the second molecule of this type caused formation of H-bonded carboranoclathrochelate dimers in the X-rayed crystal.

N-(3-Cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)-2-[[5-[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)amino]-1,3,4-thiadiazol-2-yl]sulfanyl]acetamide

The small pyrazolone-bearing molecules attract attention and are widely explored in drug design as pharmacological agents. The new pyrazolone-thiadiazole hybrid molecule N-(3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)-2-[[5-[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)amino]-1,3,4-thiadiazol-2-yl]sulfanyl]acetamide (3) has been synthesized following a two-stage protocol using simple, convenient transformations and cheap, commercially available reagents. The compound’s structure was confirmed using 1H, 13C nuclear magnetic resonance (NMR), and liquid chromatography–mass spectrometry (LC–MS) spectra. The anti-inflammatory potency of 3 was evaluated in silico using molecular docking. The docking studies results suggest that title compound 3 is of great interest for further structure optimization and in-depth studies as a possible 5-lipoxygenase (5-LOX) inhibitor.

Chemistry and Anticancer Activity of Hybrid Molecules and Derivatives Based on 5-Fluorouracil

: Cancer still continues as an important cause of death worldwide. Thus, several conventional anticancer treatments are widely used, however, most of them display low selectivity against malignant cells and induce many adverse side effects. Among these, the use of therapies based on 5-Fluorouracil (5-FU) has been one of the most efficient, with a broad-spectrum. Due to these circumstances, various modifications of 5-FU have been developed to improve drug delivery and reduce side effects. Among the optimization strategies, modifications of 5-FU at N1 or N3 position are made, usually including incorporation of pharmacological active compounds with anticancer activity (called hybrid molecule) and functionalization with other groups of compounds (called conjugates). Several studies have been conducted in the search for new alternative therapies against cancer, many of them have evidenced that hybrid compounds exhibit good anticancer activity, which has emerged as a promising strategy in this field of drug discovery and development. Furthermore, the binding of 5-FU to amino acids, peptides, phospholipids, polymers, among others, improves metabolic stability and absorption. This review highlights the potential of hybrids and derivatives based on 5-FU as a scaffold for the development of antitumor agents, besides, it also presents a detailed description of the different strategies employed to design and synthesized these compounds, together with their biological activities and Structure-Activity Relationship (SAR) analysis.

CONVENTIONAL AND MICROWAVE SYNTHESIS AND ANTIOXIDANT EVALUATION OF BENZOTHIAZOLE SUBSTITUTED 4-THIAZOLIDINONES

Antioxidants exert their action chiefly in controlling and preventing the free-radicals and their reactions and thus it has a vital role as health protecting factor. There are many scientific data proposing that antioxidants lower the threats of some chronic diseases including cancer and heart disease. In the present work, the hybrid molecule i.e benzothiazole substituted 4-thiazolidinone, has been taken for the study and different novel benzothiazole substituted 4-thiazolidinone derivatives were synthesized by reacting 2-amino-6-methyl benzothiazole with aromatic aldehydes in alcohol media. The resulting Schiff bases were made to react with thioglycolic acid in dioxane. Characterization of synthesized compounds was done by IR, 1 H NMR and Mass spectroscopy. The same reaction was performed in the microwave assisted reaction condition and compared with conventional synthesis. In vitro antioxidant activities of compounds were performed by three different methods, out of which Compound TZ4 emerged as a promising molecule.

Design of novel hybrid secondary metabolite targets to diguanylate cyclase of Acinetobacter baumannii

Biofilm formation in bacteria is a resistance determinant and is positively regulated by cyclic diguanylate signaling. This signaling is a near universal signaling, and c-di-GMP produced by diguanylate cyclase (DGC) in this signaling is involved in different bacterial behaviors. The present study aims to find a plant-based novel hybrid therapeutic agent that can target the DGC of Acinetobacter baumannii. In this study, we have tried to design a hybrid molecule from the anti-biofilm plant secondary metabolites and screened its binding with the DGC of A. baumannii. The modeled and validated DGC was used to identify the active site and docking grid. Designed hybrid compounds were analysed for their interaction with the active site residues of DGC of A. baumannii. Further, the binding free energies of the docked complexes obtained from the Generalized Born model and Solvent Accessibility (MMGBSA) were analysed. The results indicated that VR-QEg-180 has a predicted high binding affinity with enzyme DGC as compared to other hybrids, parent secondary metabolites and positive control. Molecular dynamics simulation (MDS) analysis confirmed the interaction of VR-QEg-180 with DGC of the A. baumannii. The designed lead has favorable ADMET properties, has no human off-targets and has no predicted cytotoxicity in cell lines. Therefore, the designed hybrid molecule (VR-QEg-180) targeting the DGC of A. baumannii may play a very significant role in controlling this pathogen.

Construction of an Enzymatically-Conjugated DNA Aptamer–Protein Hybrid Molecule for Use as a BRET-Based Biosensor

DNA-protein conjugates are useful molecules for construction of biosensors. Herein, we report the development of an enzymatically-conjugated DNA aptamer–protein hybrid molecule for use as a bioluminescence resonance energy transfer (BRET)-based biosensor. DNA aptamers were enzymatically conjugated to a fusion protein via the catalytic domain of porcine circovirus type 2 replication initiation protein (PCV2 Rep) comprising residues 14–109 (tpRep), which was truncated from the full catalytic domain of PCV2 Rep comprising residues 1–116 by removing the flexible regions at the N- and C-terminals. For development of a BRET-based biosensor, we constructed a fusion protein in which tpRep was positioned between NanoLuc luciferase and a fluorescent protein and conjugated to single-stranded DNA aptamers that specifically bind to either thrombin or lysozyme. We demonstrated that the BRET ratios depended on the concentration of the target molecules.