Heterocyclic Hybrids Research Articles

Design, Creation, and Biological Screening of Newer Coumarin-Coupled Heterocyclic Hybrids as Acetylcholinesterase Inhibitors that may be Useful in the Treatment of Alzheimer’s Disease

Design, Creation, and Biological Screening of Newer Coumarin-Coupled Heterocyclic Hybrids as Acetylcholinesterase Inhibitors that may be Useful in the Treatment of Alzheimer’s Disease

An Insight into Medicinal Chemistry and SAR Studies of Cholinesterase and BACE-1 Inhibitors for Alzheimer's Disease.

Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors. Researchers have conducted a detailed analysis of in vitro, in silico, and in vivo data, incorporating extensive Structure-Activity Relationship (SAR) studies. The reviewed papers have been sourced from platforms, such as Google Scholar, Semantic Scholar, and ClinicalTrials.gov, and have been selected based on their AChE and BACE-1 inhibitory activity and structural motif similarity. The review identifies the most effective compounds targeting ChE and BACE-1, highlighting acridine, dihydropyridine, and thiazole-coumarin hybrids for ChE inhibition, and oxadiazole, benzofuran, and dihydropyrimidinone for BACE-1 inhibition. This demonstrates a diverse array of potent heterocyclic hybrids. The review presents a varied compilation of scaffolds showing promise in treating Alzheimer's disease, highlighting the potential of specific compounds against ChE and BACE-1. Given the critical insights derived from our analysis, we posit that this compilation will substantially contribute to the ongoing efforts to combat neurodegeneration and prolong dementia, underscoring the importance of continuous research in this domain.

Design and synthesis of mono/bis isoxazoline and pyrroline pendant chromone derivatives-anti-cancer activity

A simple and efficient route for the synthesis of a series of new mono/bis isoxazolines, and pyrroline linked chromone heterocyclic hybrids has been developed from 2-aminochromone via key intermediate mono and 2-(diallylamino)chromen-4-one. The intermediate subjected to the [1,3] dipolar cycloaddition with insitu generated nitrile oxides and ring-closing metathesis to generate the regio selective Isoxazolines and 3-pyrrolines. All the derivatives were screened for their anti-cancer activity (Cell viability), compared to the standard drug Imatinib. Compounds 13b and 13e, 14b and 14g showed good inhibition at 10 µM concentration.

Synthesis of Novel Spirochromanone/1,2,3-Triazole Hybrid Heterocycles as Potential Antimicrobial Agents

Synthesis of Novel Spirochromanone/1,2,3-Triazole Hybrid Heterocycles as Potential Antimicrobial Agents

Synthesis, Characterization, DFT mechanistic study, Antibacterial Activity, Molecular modeling, and ADMET properties of novel chromone-isoxazole hybrids

A series of novel hybrid heterocycles incorporating isoxazole rings have been successfully synthesized, characterized, and evaluated for their antibacterial responses. The synthesized compounds were obtained by a subsequent N-alkylation and 1,3-dipolar cycloaddition reactions, their structures were identified by spectroscopy techniques (1H NMR, 13C NMR and 2D HSQC), and confirmed by mass spectrometry (HRMS). The spectroscopic data also show that the 1,3-dipolar cycloaddition (1,3-DC) reactions proceed in a regiospecific manner to give only one cycloadduct. The observed regioselectivity and the mechanistic study of the 1,3-DC reaction were further highlighted and explained using Density Functional Theory (DFT) calculations with the B3LYP/6–31G(d,p) basis set and Electron Localization Function (ELF) analysis. Moreover, the antibacterial screening shows that some compounds exhibit good efficacy against the tested bacterial strains. In addition, molecular docking studies were carried out to highlight the modes of interaction between the most active molecule 5d and receptors of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus strains. The results show that the studied compound was effectively docked to the active sites of each responsible protein with high protein-binding energies in kcal/mol. Finally, the prediction of ADMET properties suggests that almost all the hybrid compounds have good pharmacokinetic profiles, with no observed signs of toxicity, except for compounds 5e, 5f and 5g.

Facile synthesis and in silico studies of benzothiazole-linked hydroxypyrazolones targeting α-amylase and α-glucosidase.

Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a-t, were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.

Development in the Synthesis of Bioactive Thiazole-Based Heterocyclic Hybrids Utilizing Phenacyl Bromide.

Heterocyclic hybrid frameworks represent a burgeoning domain within the realms of drug discovery and medicinal chemistry, attracting considerable attention in recent years. Thiazole pharmacophore fragments, inherent in natural products such as peptide alkaloids, metabolites, and cyclopeptides, have demonstrated a broad spectrum of pharmacological potentials. Given their profound biological significance, a plethora of thiazole-based hybrids have been synthesized through the conjugation of thiazole moieties with bioactive pyrazole and pyrazoline fragments. This review systematically presents a compendium of robust methodologies for the synthesis of thiazole-linked hybrids, employing the (3 + 2) heterocyclization reaction, specifically the Hantzsch-thiazole synthesis, utilizing phenacyl bromide as the substrate. The strategic approach of molecular hybridization has markedly enhanced drug efficacy, mitigated resistance to multiple drugs, and minimized toxicity concerns. The resultant thiazole-linked hybrids exhibit a myriad of medicinal properties viz. anticancer, antibacterial, anticonvulsant, antifungal, antiviral, and antioxidant activities. This compilation of methodologies and insights serves as a valuable resource for medicinal chemists and researchers engaged in the design of novel thiazole-linked hybrids endowed with therapeutic attribute.

Synthesis and Biological Activities of Heterocyclic Hybrids Containing Piperidine and Pyridine Moieties: Recent Developments

Abstract: Piperidine and pyridine nuclei are essential heterocyclic systems and act as an essential underpinning for agriculture, medicines, industries, etc. The development of novel methods for the synthesis of these exemplary heterocyclic compounds and their respective hybrids, which show a wide range of biological activities, is a very fascinating theme. The derivatives of these pervasive nuclei are used as antibacterial, antimicrobial, antifungal, antimalarial, anticancer, antiproliferative, antihypertensive, antiparasitic, and many other agents. The hybrids of these nuclei have retained a distinct position in medicinal chemistry and are often incorporated in synthetic drug discovery. In this review, we have compiled relevant literature on different derivatives of piperidine and pyridine moieties and their biological activities.

Oxacyanopyridine-Benzofuran Hybrids: Synthesis, in silico Toxicity Assessment, in vitro Antimicrobial Activity and Dual Target Docking Studies

This study emphasizes the synthesis and characterization of a novel series of oxa cyano pyridine heterocyclic molecular hybrids (OCP 1-6), integrating pyridine and benzofuran motifs. Meticulously designed from 5-chlorosalicylaldehyde in a multistep process, the synthesized compounds were structurally confirmed through IR spectroscopy, 1H NMR spectroscopy, and mass spectrometry. Computational predictions highlighted diverse properties, including antitubercular and antibacterial attributes, bioactivity scores, toxicity profiles and potential molecular targets. In vitro assessments and Schrödinger docking simulations revealed binding affinities to enzymes viz. Mycobacterium tuberculosis enoyl-ACP reductase and Escherichia coli Topoisomerase IV. Compounds, particularly OCP 2, 3, 4 and 5, exhibited significant antitubercular and antibacterial activities in both in vitro assessments and docking simulations. This study underscores the substantial potential of the synthesized hybrids as promising candidates for further lead optimization, positioning them as valuable contributors to the development of pharmaceutical agents with heightened potency and enhanced safety profiles.

Synthesis, Antimicrobial Activity and Molecular Docking of Some Novel 2-Aryl-4H-[1,3]-thiazolo[4,5-b]indoles

In present study, six novel 2-aryl-4H-[1,3]-thiazolo[4,5-b]indoles (4a-f) were synthesized by integrating thiazole and indole motifs through a three-component one-pot condensation involving isatin, ammonium thiocyanate and arylaldehydes. Structural confirmation was achieved using IR, 1H NMR and mass spectrometric techniques. Molecular targets, bioactivity scores, drug-likeness, anti- tuberculosis and antibacterial properties and toxicity were all predicted using various computational techniques. To calculate binding affinities to Mycobacterium tuberculosis enoyl-ACP reductase and Escherichia coli Topoisomerase IV, in vitro bioactivity studies were performed and Schrödinger docking simulations were performed. Anti-tubercular efficacy was evaluated using the MABA method, while antibacterial effectiveness against both Gram-positive and Gram-negative bacteria was assessed through the agar plate method. The results highlight the potential of these heterocyclic molecular hybrids, positioning them as promising candidates for further lead optimization in the development of more potent and safer pharmaceutical agents.

Piperazine tethered heterocyclic hybrids: Synthesis, characterization, and in vitro studies from potent proteinase inhibitors to antiproliferative activity

This study reports the synthesis and evaluation of the biological activity of a new series of piperazine analogues (PA) containing heterocyclic moieties. Structural analogies of all four novel synthesized drug candidates were confirmed using FT-IR, 1H-NMR, and HPLC- MS spectral analysis. The antimicrobial activity of all synthesized piperazine analogues was evaluated against Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans using the agar well diffusion method. PA-2 and PA-3 exhibited strong antimicrobial activity against all tested pathogens, comparable to the standard. However, dose-dependent antimicrobial behaviour was observed for PA-4, while all three strains displayed strong resistance against, PA-1. The antioxidant activity of synthesized derivatives was assessed using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The in vitro antioxidant activity results demonstrated that PA-3 displayed remarkable antioxidant activity with IC50 of 0.77 μg/mL compared to control (Gallic acid_0.75 μg/mL). PA-1 and PA-2 exhibited moderate antioxidant activity, while PA-4 showed the lowest antioxidant properties. Piperazine analogues were further investigated for their anti-inflammatory and antiproliferative activities using Proteinase Inhibitory Action and MTT assay against two breast cancer cell lines (MCF-7; MDA-MB-231). Results notified that PA-3 demonstrated encouraging anti-inflammatory (IC50 = 0.68 μg/mL) and antiproliferative (IC50 = 33.8 μg/mL) activities. The flow cytometric approach indicated that PA-4 raised the levels of H2DCFDA, signifying its cytotoxic nature against MDA- MB-231 cells. Furthermore, a gene expression analysis against CAIX gene (Hypoxia-regulated carbonic anhydrase- 9) as the target revealed that PA-3 significantly reduced the expression of CAIX genes in MDA-MB-231 cells, specifying a pronounced down-regulation effect on CAIX genes by PA-3. These results highlight the potential of the synthesized piperazine analogue PA- 3 as a promising candidate for further investigation in developing an anti-breast cancer drug against triple-negative breast cancer cells.

Hybrid Heterocycles: Ag(I)-Catalyzed C-C/C-N/C-O Coupled Cascade Dual Cyclization to Valuable Indolo-4H-indolones and Indolo-4H-chromenes.

Herein, we report a highly efficient Ag(I)-catalyzed indolyzation with Friedel-Crafts alkylation through a cascade cyclization strategy for accessing valuable hybrid heterocycles for the first time. This general strategy consists of forming four C-C/C-N/C-O bonds toward dual annulation reactions of 2-alkynylanilines with methyl benzoate-2-carboxaldehydes and aromatic amines, as well as with salicylaldehydes and malononitrile. Variably substituted new indolo-4H-phthalimidines and indolo-4H-chromenes were synthesized with excellent yields (85-93%) under mild reaction conditions.

Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents.

Two different synthetic approaches to novel heterocyclic hybrid compounds of 4-azapodophyllotoxin were investigated. The obtained products were characterized by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. MTT protocol was then performed to examine the cytotoxic activity of these products against KB, HepG2, A549, MCF7, and Hek-293 cell lines. The cytotoxic assessment indicated that all products displayed moderate to high cytotoxicity against all tested cancer cell lines. The most active compound 13k containing the 2-methoxypyridin-4-yl group exhibited selective cytotoxicity against KB, A549, and HepG2 cell lines with the IC50 values ranging from 0.23 to 0.27 μM, which were between 5- to 10-fold more potent than the positive control ellipticine. Compounds 13a (HetAr = thiophen-3-yl) and 13d (HetAr = 5-bromofuran-2-yl) displayed high cytotoxic selectivity for A549 and HepG2 cancer cell lines when compared to the other cancer cell lines and low toxicity to the normal Hek-293 cell line. Molecular docking study was conducted to evaluate the interaction of new synthesized compounds with the colchicine-binding-site of tubulin. Besides that, physicochemical and pharmacokinetic properties of the most active compounds 13h,k were predicted.

Synthesis, computational docking and molecular dynamics studies of a new class of spiroquinoxalinopyrrolidine embedded chromanone hybrids as potent anti-cholinesterase agents.

Novel structurally intriguing heterocycles embedded with spiropyrrolidine, quinoxaline and chromanone units were synthesized in good yields using a [Bmim]Br accelerated multicomponent reaction strategy. The key step of the reaction is 1,3-dipolar cycloaddition involving highly functionalized dipolarophile, viz. 3-benzylidenechroman-4-one, to afford spiroquinoxalinopyrrolidine embedded chromanone hybrid heterocycles. The formation of spiro products occurs via two C-C, two N-C and one C-N bonds possessing four adjoining stereogenic centers, two of which are spiro carbons. The newly synthesized spiro compounds showed potent acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, compounds with fluorine displayed the highest AChE (3.20 ± 0.16 μM) and BChE (18.14 ± 0.06 μM) inhibitory activities. Further, docking studies, followed by all-atom molecular dynamics, showed results that are consistent with in vitro experimental findings. Although docking scores for the synthesized derivatives were higher than those of the standard drug, MD MMPBSA results showed better binding of synthesized derivatives (-93.5 ± 11.9 kcal mol-1) compared to the standard drug galantamine (-66.2 ± 12.3 kcal mol-1) for AChE but exhibited similar values (-98.1 ± 11.2 and -97.9 ± 11.5 kcal mol-1) for BChE. These differences observed in drug binding with AChE/BChE are consistent with RMSD, RMSF, LIG plots, and FEL structural analysis. Taken together, these derivatives could be potential candidates as inhibitors of AChE and BChE.

Activity against Mycobacterium tuberculosis of a new class of spirooxindolopyrrolidine embedded chromanone hybrid heterocycles.

A new class of structurally intriguing heterocycles embedded with spiropyrrolidine, oxindole and chromanones was prepared by regio- and stereoselectively in quantitative yields using an intermolecular tandem cycloaddition protocol. The compounds synthesized were assayed for their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv and isoniazid-resistant (katG and inhA promoter mutations) clinical Mtb isolates. Four compounds exhibited significant antimycobacterial activity against Mtb strains tested. In particular, a compound possessing a fluorine substituted derivative displayed potent activity at 0.39 μg mL-1 against H37Rv, while it showed 0.09 μg mL-1 and 0.19 μg mL-1 activity against inhA promoter and katG mutation isolates, respectively. A molecular docking study was conducted with the potent compound, which showed results that were consistent with the in vitro experiments.

Benzofuran-Isoxazole Hybrids: Synthesis, Antimicrobial Activity and Dual Target Docking Studies

In this study, five novel heterocyclic molecular hybrids (4a-e) were synthesized by combining benzofuran and isoxazole motifs. Thesecompounds were synthesized via a multistep process starting with 5-chlorosalicylaldehyde. The structures of the synthesized compounds were characterized by IR, 1H NMR and mass spectrometry. Computational tools were employed to predict properties, including antitubercular and antibacterial traits, drug-likeness, bioactivity scores, toxicity and potential molecular targets. In addition to these predictions, in vitro bioactivities were assessed and conducted Schrödinger docking simulations to determine binding affinities to Mycobacterium tuberculosis enoyl-ACP reductase and Escherichia coli topoisomerase IV. Antitubercular efficacy was determined via the MABA method, while antibacterial effectiveness was tested against both Gram-positive and Gram-negative bacteria. The obtained results highlighted the promise of these benzofuranyl-isoxazole hybrids, making them strong contenders for further lead optimization, with the goal of developing more potent and safer pharmaceutical agents.

Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives.

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

Synthesis of Novel Series of 1,2,3-Triazoles Tethered to Pyrazolo[3,4-d]pyrimidine Scaffold with Methoxyphenoxy Linker

A novel series of hybrid heterocycles having pyrazolopyrimidine based 1,2,3-triazole scaffold with two ether linkages were synthesized by 1,3-dipolar cycloaddition reaction of pyrazolopyrimidines tethered to phenoxy alkynes and differently substituted aromatic azides using CuSO4·5H2O and sodium ascorbate mixture as catalyst in DMSO-H2O solvent mixture. The synthesized triazole hybrids were characterized by using various spectroscopic techniques.

Cholinesterase inhibitory activity and regioselective synthesis of spiropyrrolidinoindole integrated ferrocene hybrid heterocycles via multicomponent cycloaddition reaction

A novel spiroheterocyclic hybrid comprising several privileged structures comprising pyrrolidine, quinoxaline, indole and ferrocene moieties were synthesized in good yields in sustainable fashion using [Bmim]Br augmented four component cycloaddition process. A relatively less explored ylide prepared from quinoxalinone and L-tryptophan with diverse ferrocenyl derivatives in ionic liquids afforded spiropyrrolidinoindole tethered ferrocene hybrids. The reaction provides highly regioselective fashion thus created five new bonds and four adjoining stereocenter in single synthetic transformation, thus created with complete diastereomeric control. The cholinesterase inhibitory potency was performed for synthesized compounds against AChE/BChE enzymes. Among them, compound bearing with fluorine substituted heterocycles showed significant activity which is comparable activity with reference standard, galantamine.

Design, stereoselective synthesis and anticancer efficacy of a new class of functionalized pyrrolizidine heterocyclic hybrids

Eight new functionalized spirooxindole-pyrrolizidine heterocyclic hybrids has been obtained from N-pyridinylmethyl-bisarylmethylidene-pyridinones, Isatin and L-Proline by a multi-component cycloaddition reaction. Such synthesized derivatives are being characterized systematically with the aid of instrumental facilities like FT-IR, NMR spectroscopy, and Mass spectrometry. Following this, all the compounds are tested for the anticancer potentials in vitro using HepG2 cells (cancer cells). The compound with no substitution on the aryl rings (phenyl rings), displayed the highest activity among the spirooxindole-pyrrolizidines. Further the most active heterocyclic hybrids are verified for toxicity effects against L929 cells (non-cancer cells; at 200 µg/mL for 24 h). Finally, the cell viability losses for these most active compounds (at its IC50 value) are addressed by assaying the activity of free radicals, apoptosis, and caspases.