Hybrid Analogues Research Articles

Synthesis of Natural Product‐like Indeno[2,1‐b]indole/Shikimic Acid Hybrid Analogues with Anti‐osteoclastogenic Activity via Photo‐Nazarov Reaction

AbstractIndeno[2,1‐b]indole and shikimic acid‐like structures are natural privileged scaffolds in several bioactive NPs. In this work, we developed a high‐efficient and diastereoselective synthetic approach to construct novel indeno[2,1‐b]indole/shikimic acid hybrid analogues via photo‐Nazarov reaction. The protocol is the first case of excited‐state photo‐Nazarov cyclization of indole‐2‐yl vinyl ketone to indeno[2,1‐b]indole. (6aS, 10aR)‐products were afforded in moderate to good yields (37–92 %) for most of substrates (91 % for model substrate 1 aa) after the condition optimization. Even more attractive, several synthesized analogues (2 t, 3 c and 3 d) exhibited potent RANKL‐induced osteoclastogenesis inhibitory activities (inhibitory rate >50 % at 5 μM), which suggested promising prospect of the novel tetracyclic indeno[2,1‐b]indole/shikimic acid hybrid scaffold for anti‐osteoporosis drug development.

A Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aβ) in the form of Aβ plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-β (Aβ) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.

Synthesis of novel indazole derivatives as inhibitors of diabetics II along with molecular docking and simulation study

In the light of the pharmacological significance of the indazole and 1, 3, 4-thiadiazole scaffold, hybrid analogs of indazole and 1, 3, 4-thiadiazole (1–14) were synthesized, identified using HREI-MS, 1H, and 13CNMR, and their capability for inhibition of α-amylase and α-glucosidase enzymes was evaluated. Generally, most of the synthesized derivatives of the series exhibited good inhibition activity in comparison to the reference drug acarbose with IC50 value of 10.30 ± 0.20 for α-amylase, and 9.80 ± 0.20 for α-glucosidase. Amongst the synthesized derivatives, fluoro substituted analog 10 appeared to be the most potent inhibitor having IC50 value of 9.90 ± 0.30 for α-amylase and 9.20 ± 0.30 for α-glucosidase. A structure activity relationship (SAR) for the series was established based on electronic effects and the positions of various groups on the phenyl ring. To comprehend the chemicals' binding interactions, molecular docking along with simulation study were also carried out. Compound 10 was ranked top in the series based on docking score and interactions with receptors. Compound 10 establish more H-bond contacts with the active site's residue of alpha-amylase and α-glucosidase as compared to all other compounds. Furthermore, 10 was found to be highly stable throughout 50 ns MD simulation. As compared to the control drug, 10 revealed high stability with both α-amylase and α-glucosidase enzymes during molecular dynamics simulation.

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid β (Aβ) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheseshave been proposed, including the cholinergic, Aβ, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aβ hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

Hybrid Analogues of Hydrazone and Phthalimide: Design, Synthesis, In vivo, In vitro, and In silico Evaluation as Analgesic Agents.

Based on the anti-inflammatory and analgesic activity of hydrazone and phthalimide, a new series of hybrid hydrazone and phthalimide pharmacophores was prepared and evaluated as analgesic agents. The designed ligands were synthesized by reaction of the appropriate aldehydes and 2- aminophthalimide. Analgesic, cyclooxygenase inhibitory, and cytostatic activity of prepared compounds were measured. All the tested ligands demonstrated significant analgesic activity. Moreover, compounds 3i and 3h were the most potent ligands in the formalin and writhing tests, respectively. Compounds 3g, 3j, and 3l were the most COX-2 selective ligands and ligand 3e was the most potent COX inhibitor with a 0.79 of COX-2 selectivity ratio. The presence of electron-withdrawing moieties with hydrogen bonding ability at the meta position was found to affect the selectivity efficiently, in which compounds 3g, 3l, and 3k showed high COX-2 selectivity, and compound 3k was the most potent one. The cytostatic activity of selected ligands demonstrated that compounds 3e, 3f, 3h, 3k, and 3m showed good analgesic and COX inhibitory activity and were less toxic than the reference drug. High therapeutic index of these ligands is one of the valuable advantages of these compounds.

A promising α-glucosidase and α-amylase inhibitors based on benzimidazole-oxadiazole hybrid analogues: Evidence based in vitro and in silico studies

The present study reports the design and synthesis of new benzimidazole-oxadiazole compounds as potent inhibitors of α-glucosidase and α-amylase. The synthesized molecules were characterized through different techniques such as 1HNMR, 13CNMR, HREI-MS and evaluated for their in vitro inhibitory activities against these enzymes. Among the compounds screened, compound 8 demonstrated the highest inhibitory activity against both α-glucosidase (IC50 = 11.60 µM) and α-amylase (IC50 = 6.20 µM). Molecular docking analyses were conducted to investigate the binding modes and interactions of the active compounds within the enzyme active sites. The results demonstrate that several benzimidazole-oxadiazole hybrids exhibited potent inhibitory effects on both α-glucosidase and α-amylase, suggesting their promise as antidiabetic agents.

Design, synthesis, biological evaluation and molecular docking study of thiadiazole-isatin hybrid analogues as potential anti-diabetic and anti-bacterial agents

We have synthesized thiadiazole-isatin hybrid analogues (1–20), characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, HREI-MS, and evaluated against α-glucosidase and α-amylase enzymes. All analogues showed potent inhibitory potentials, having an IC50 values ranged from 22.08 ± 0.09 to 54.03 ± 0.07 μM (against α-amylase) and 19.03 ± 0.04 to 50.03 ± 0.02 μM (α-glucosidase) when compared with the standard drug acarbose (IC50 = 22.07 ± 0.02 μM for α-amylase and IC50 = 18.01 ± 0.06 μM for α-glucosidase respectively). Among the series, analogues 13 (IC50 = 19.03 ± 0.04 and 22.08 ± 0.09 μM), 12 (IC50 = 21.03 ± 0.07 and 24.03 ± 0.07 μM), and 5 (IC50 = 22.02 ± 0.03 and 26.02 ± 0.04 μM) were identified as the most active inhibitors. The structure–activity relationship was carried out, mainly associated with the nature, number, position, and electron-donating and electron-withdrawing effects of the substituent (s) on the phenyl ring. With the help of molecular docking, the binding interaction of the most active analogues within the active site of enzymes was confirmed. Almost twelve compounds were also screened for antibacterial potential, and few were found to be effective against Bacillus subtilis. All compounds were verified for cytotoxicity against the 3 T3 mouse fibroblast cell line and detected non-toxic.

Discovery of Dual TRPA1 and TRPV1 Antagonists as Novel Therapeutic Agents for Pain.

Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound 50 exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC50 values of 1.42, 2.84, 2.13, and 5.02 μM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound 50 demonstrated dose-dependent analgesic activity with an ED50 of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management.

Synthesis, biological and computational evaluation of benzoxazole hybrid analogs as potential anti-Alzheimer's agents.

Aim: Current study aims exploration of bis-benzoxazole bearing bis-Schiff base scaffolds (1-16) as anti-Alzheimer's agents.Materials & methods: 2-aminophenol is used as starting materials which react with different reagents in different step to give us bis-benzoxazole bearing bis-Schiff base analogs. NMR and HREI-MS techniques were used for characterization. All derivatives demonstrated varied range of activities with IC50 values 1.10±0.40-24.50±0.90μM against acetylcholinesterase (AChE) and 1.90±0.70-28.60±0.60μM against butyrylcholinesterase (BuChE) in contrast to donepezil. In both cases, analog-3 was found most potent. Molecular docking explored modes of interactions between scaffolds and receptor sites of targeted enzymes.Conclusion: This study offering promising approach for optimization and development of potent inhibitors of cholinesterase enzymes.

Medicinal perspectives, molecular docking and structure activity relationship of benzothiazole derived thiazole-based bis-benzohydrazide as potential anti-Alzheimer agents

A new series of benzothiazole derived thiazole-based bis-benzohydrazide hybrid (1–20) analogs were synthesized. Initially, the product confirmation was identified by employing TLC and the basic skeleton of the new hybrid synthesized compounds was further confirmed through spectroscopic techniques such as 13CNMR, 1HNMR and HREI-MS. Moreover, the synthesized analogs were tested for their inhibitory activities against acetylcholinesterase and butyrylcholinesterase. In the whole series, compounds 1, 2, 3 and 6 were found with potent activity against acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE). Molecular docking inveatigation of the potent compounds was performed within the active site of acetylcholinesterase and butyrylcholinesterase revealing compounds 1, 2, 3 and 6 showing promising binding orientations against both enzymes as compared to reference drug donepezil with their IC50 values 1(2.20 ± 1.40 and 3.18 ± 0.45 μM), 2 (2.89 ± 1.25 and 2.78 ± 1.49 μM), 3 (2.94 ± 1.10 and 3.07 ± 1.23 μM), 6 (5.83 ± 1.45 and 6.03 ± 3.08 μM), respectively, and reference drug (IC50 = 8.73 ± 2.68 and 9.30 ± 2.60 μM for acetylcholinesterase and butyrylchlinesterase, respectively. In addition, ADME studies were conducted to gain a deeper understanding of the functional mechanisms of a drug on a living organism. It is considered that benzothiazole derived thiazole based bis-benzohydrazide hybrid analogs (1, 2, 3, 6) might be better inhibitors of acetylcholinesterase and butyrylcholinesterase enzymes.

Tetrahydropyridine appended 8-aminoquinoline derivatives: Design, synthesis, in silico, and in vitro antimalarial studies

Antimalarial drug resistance is a major obstacle in the ongoing quest against malaria. The disease affects half of the world’s population. The majority of them are toddlers and pregnant women. Needed a potent compound to act on drug-resistant Pf at appropriate concentrations without endangering the host. Envisaged solving this issue through rational drug design by creating a novel hybrid drug possessing two pharmacophores that can act on two marvellous and independent aims within the cell. Synthesized a new series of substituted 4-phenyl-1,2,3,6-tetrahydropyridine (THP) 8-Aminoquinoline-based hybrid analogs which have been integrated with quinoline, chloroquine, pamaquine, and primaquine, which exhibited antimalarial activity against Pf. Out of thirteen 4-phenyl-1,2,3,6-THP appended 8-Aminoquinoline derivatives, the compounds 1j, 1e, 1b, and 1l have exhibited good antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strain with the minimum inhibitory concentration. Compound 1b was the most effective and showed consistently good potency against the drug-resistant (RKL-9) strain, although all other arrays showed good antimalarial efficacy. Additional docking and molecular dynamics studies were carried out at several targeting sites to quantify the structural parameters necessary for the activity.

Synthesis, in vitro β-glucuronidase inhibition of benzoxazole bearing thiosemicarbazide derivatives along with in silico molecular docking study

This study was aimed to design and synthesize hybrid analogues of benzoxazole bearing thiosemicarbazide analogues 1–15 as promising β-Glucuronidase inhibitory activity using D-saccharic acid 1,4-lactone as the reference inhibitor. The newly afforded benzoxazole-thiosemicarbazide compounds 1–15 displayed a broad range of inhibitory potential with IC50 values ranging from 20.58 ± 2.46 to 87.89 ± 8.43 μM, as compared to D-saccharic acid 1,4-lactone (IC50 = 59.5 ± 5.36 μM). Among the synthesized series, the compounds 14, 2, and 5 demonstrated outstanding β-Glucuronidase inhibitory potential with IC50 values of 20.58 ± 2.46, 25.24 ± 2.34 and 24.53 ± 2.53 μM respectively. Further, the precise structures of synthesized analogues were confirmed using 1H NMR, 13C NMR and HREIMS. Additionally, the molecular docking approach was employed to correlate the in vitro β-Glucuronidase inhibitory activity well with in silico study and result obtained corroborated that active analogues established several key interactions with the active sites of β-Glucuronidase enzyme.

Transition‐Metal‐Free Annulation of Sulfonyl‐Derived 1,3‐Enynes: Simple and Efficient Construction of 2,4‐Disubstituted Thiophenes and Vinyl Sulfone‐Tethered 1,2,3‐NH‐Triazoles

AbstractThiophenes and 1,2,3‐NH‐triazoles are important frameworks in pharmaceuticals and advanced functional materials. Vinyl sulfones are also blueprint motifs in medicinal chemistry, but hybrid analogues of 1,2,3‐NH‐triazole‐derived from vinyl sulfones still need to be explored. In this report, we present an efficient and transition‐metal‐free [4+1]‐thioannulation of sulfonyl‐tethered 1,3‐enynes with Na2S in the presence of Cs2CO3 to generate 2,4‐disubstituted thiophenes in good to high yields. We also established a formal [3+2]‐cycloaddition of 1,3‐sulfonylenynes with NaN3 under metal‐ and base‐free conditions to synthesize vinyl sulfone‐containing 1,2,3‐NH‐triazole derivatives in moderate to high yields. The scope of these protocols was successfully showcased with various types of 1,3‐enynes bearing sensitive functional groups and complex structural scaffolds. The desired products were readily obtained with good functional group tolerance and compatibility. Based on the existing results and control experiments, plausible mechanistic pathways are also presented.

Recent development and strategies towards target interactions: Synthesis, characterization and in silico analysis of benzimidazole based thiadiazole as potential anti-Alzheimer agents

In the current research study, we aim to design and synthesize highly potent hybrid analogs of benzimidazole derived thiadiazole based Schiff base derivatives which can combat the cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase) accountable for developing Alzheimer's disease. In this context, we have synthesized 15 analogs of benzimidazole based thiadiazole derivatives, which were subsequently confirmed through spectroscopic techniques including 1H NMR, 13C NMR and HREI-MS. Biological investigation of all the analogs revealed their varied acetylcholinesterase inhibitory potency covering a range between 3.20 ± 0.10 μM to 20.50 ± 0.20 μM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 ± 0.50 μM to 20.70 ± 0.50 μM when compared with the standard drug Donepezil having IC50 = 6.70 ± 0.20 μM for AChE and 7.90 ± 0.10 μM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC50 = 3.20 ± 0.10 μM for AChE and 4.30 ± 0.50 μM for BuChE), analog-4 (IC50 = 4.30 ± 0.30 μM for AChE and 5.50 ± 0.20 μM for BuChE) and analog-5 (IC50 = 4.10 ± 0.30 μM for AChE and 4.60 ± 0.40 μM for BuChE) were found as the lead candidates. Moreover, molecular docking and ADME analysis were conducted to explore the better binding interactions and drugs likeness respectively.

Green Approach Toward Triazole Forming Reactions for Developing Anticancer Drugs.

Compounds containing triazole have many significant applications in the dye and ink industry, corrosion inhibitors, polymers, and pharmaceutical industries. These compounds possess many antimicrobial, antioxidant, anticancer, antiviral, anti-HIV, antitubercular, and anticancer activities. Several synthetic methods have been reported for reducing time, minimizing synthetic steps, and utilizing less hazardous and toxic solvents and reagents to improve the yield of triazoles and their analogues synthesis. Among the improvement in methods, green approaches towards triazole forming biologically active compounds, especially anticancer compounds, would be very important for pharmaceutical industries as well as global research community. In this article, we have reviewed the last five years of green chemistry approaches on click reaction between alkyl azide and alkynes to install 1,2,3-triazole moiety in natural products and synthetic drug-like molecules, such as in colchicine, flavanone cardanol, bisphosphonates, thiabendazoles, piperazine, prostanoid, flavonoid, quinoxalines, C-azanucleoside, dibenzylamine, and aryl-azotriazole. The cytotoxicity of triazole hybrid analogues was evaluated against a panel of cancer cell lines, including multidrug-resistant cell lines.

Investigation of novel benzimidazole-based indole/thiazole hybrids derivatives as effective anti-diabetics and anti-alzheimer's agents: Structure-activity relationship insight, in vitro and in silico approaches

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are common in developed countries and their incidence is increasing. The research is mostly concentrated on the exploration of novel therapies to remedy or avert these ailments. AD and T2DM have several molecular pathways in common that contributes to their degenerative development. A novel series of ten hybrid analogues (1–10) based on benzimidazole bearing indole analogues were synthesized and these scaffolds were characterized by spectroscopic techniques like HR-EIMS, 13CNMR and 1HNMR. Furthermore, the synthesized moieties were screened for α-amylase and α-glucosidase inhibitory activities. All these synthesized analogues showed good to moderate α-amylase and α-glucosidase inhibition potency ranging (4.90 ± 0.10 to 15.30 ± 0.60 µM) and (5.30 ± 0.10 to 16.10 ± 0.60 µM) while acarbose was used as a reference standard (IC50 = 10 0.30 ± 0.20 µM), (IC50 = 9.80 ± 0.20 µM). Another series of ten hybrid analogues (11–20) based on benzimidazole bearing thiazole moieties were synthesized and were evaluated for AChE and BuChE inhibition activities. All these newly afforded analogues showed good to moderate AChE and BuChE inhibitory potential ranging of (IC50 = 0.20 ± 0.01 µM), (IC50 = 0.15 ± 0.01 µM) to (IC50 = 3.90 ± 0.20 µM), (IC50 = 3.80 ± 0.10 µM) while Donepezil was taken as a reference standard with (IC50 = 0.016 ± 0.01 µM), (IC50 = 0.30 ± 0.010 µM).The scaffolds were also characterized using spectroscopic techniques such as HR-EIMS, 13CNMR and 1HNMR for a better understanding of their structure. SAR was done for all synthesized analogues for substituents.In addition, docking research was conducted to determine the binding mode of interaction between the active site of analogues and targeted enzymes. This work aims to estimate the potential of the synthesized scaffolds as competitors to existing drugs. Incorporating molecular docking analysis with in vitro activities improves the accuracy of predictions and validates the possibility of these compounds as options for treating type-2 diabetes and Alzheimer's disease.

Correlation between in vitro anti-urease activity and in silico molecular modeling approach of novel imidazopyridine–oxadiazole hybrids derivatives

Abstract In the current era, a potent drug is still needed on the market for the treatment of various diseases worldwide. Researchers mainly focus on those enzymes that cause these diseases. One of the major diseases is caused by an enzyme called urease, which increases the concentration of ammonia in the body upon hydrolysis. Researchers across the globe have keen interest to synthesize the potent inhibitor for this conversion. From this perspective, hybrid analogs of imidazopyridine and oxadiazole (1–20) were designed and efficiently synthesized followed by characterizing them through varied spectroscopic methods (1HNMR, 13CNMR, and HREI-MS). In addition, in vitro analyses of the synthesized compounds were conducted to evaluate their anti-urease potency. There was significant potential in most compounds analyzed, but analogs 15, 16, and 17 (IC50 = 2.20 ± 0.10 μM, IC50 = 2.50 ± 0.10 μM, and IC50 = 2.30 ± 2.10 μM, respectively) performed exceptionally well in comparison with thiourea (IC50 = 22.30 ± 0.44 μM). The selected candidates were further investigated under a molecular docking study to confirm protein ligand interactions. In addition, energy gap (E gap) of the HOMO–LUMO was explored via density functional theory studies.

Design, Synthesis and Biological Evaluation of Biphenyl-1,2,3-Triazole Hybrid Analogues as PD-1/PD-L1 Inhibitors

Design, Synthesis and Biological Evaluation of Biphenyl-1,2,3-Triazole Hybrid Analogues as PD-1/PD-L1 Inhibitors

A Series of Bimetallic Ammonium RbEu Nitrates Exhibiting Switchable Dielectric Constant and Photoluminescence Property

A series of RbEu bimetallic ammonium metal nitrate hybrid analogues, [(CH3)3NCH2X]2[RbEu(NO3)6] (X = Cl, 1; Br, 2; I, 3), have been synthesized via solvent evaporation. This series shows similar cage-like...

A relay ring-closing metathesis/Diels-Alder approach to sugar-derived pluramycin-hybrids.

Herein, we present a general approach for synthesizing pluramycin hybrids, which are analogous to the pluramycinone carbocyclic skeleton. This method involves a sequence of relay ring-closing enyne metathesis, Diels-Alder and oxidative aromatization reactions to synthesize pluramycinone-sugar hybrids. As part of our ongoing research, we have successfully synthesized two pluramycin hybrid analogues by carefully monitoring the late-stage oxidative aromatization steps, which depend on the stereo-orientation of the Diels-Alder cycloadduct at the C-4 center. The undesired ring-opening product can also serve as a C-glycoside analog, providing a versatile convergent route to access both types of hybrids and highlighting the significance of this strategy.