Molecular Hybridization Research Articles

Molecular hybridization modification improves the stability and immunomodulatory activity of TP5 peptide

Thymopentin (TP5) plays an important role in host immunomodulation, yet its bioavailability is significantly limited by its short half-life. YW12D is a peptide with strong stability but relatively weak immunoactivity. Tuning the physicochemical properties of such molecules may yield synthetic molecules displaying optimal stability, safety and enhanced immunological activity. Here, natural peptides were modified to improve their activity by hybridization strategies. A hybrid peptide YW12D-TP5 (YTP) that combines TP5 and YW12D is designed. The half-life of YTP in plasma is significantly longer than that of YW12D and TP5. YTP also displays an improved ability to protect the host from CTX-induced weight loss and thymus and spleen indices decrease than YW12D and TP5. In addition, YTP promotes dendritic cell maturation and increases the expression of cytokines IL-1β, IL-6, TNF-α and immunoglobulins IgA, IgG, and IgM. A combination of antibody-specific blocking assay, SPR, molecular dynamics simulations and western blotting suggest that the immunomodulatory effect of YTP is associated with its activation of the TLR2-NF-кB signaling axis. In sum, we demonstrate that peptide hybridization is an effective strategy for redirecting biological activity to generate novel bioactive molecules with desired properties.

Synthesis, Molecular Docking, and Biological Evaluation of Novel Indole-triazole Conjugates.

Indole-triazole conjugates have emerged as promising candidates for new drug development. Their distinctive structural characteristics, coupled with a wide array of biological activities, render them a captivating and promising field of research for the creation of novel pharmaceutical agents. This study aimed to synthesize indole-triazole conjugates to investigate the influence of various substituents on the functional characteristics of indole-triazole hybrids. It also aimed to study the binding modes of new hybrids with the DNA Gyrase using molecular docking studies. A new set of indole-triazole hybrids was synthesized and characterized using various physicochemical and spectral analyses. All hybrids underwent in-silico pharmacokinetic prediction studies. The antimicrobial efficacy of the hybrids was assessed using tube dilution and agar diffusion methods. Additionally, the in-vitro antioxidant activity of synthesized compounds was determined using the 1,1-diphenyl-2-picryl-hydrazyl free radical scavenging assay. Furthermore, in silico molecular docking studies were performed to enhance our comprehension of how the synthesized compounds interact at the molecular level with DNA gyrase. Pharmacokinetic predictions of synthesized hybrids indicated favourable pharmacokinetic profiles, and none of the compounds violated the Lipinski rule of five. Notably, compound 6, featuring a cyclohexanol substituent, demonstrated superior antimicrobial and antioxidant activity (EC50 value = 14.23 μmol). Molecular docking studies further supported the in vitro antioxidant and antimicrobial findings, revealing that all compounds adeptly fit into the binding pocket of DNA Gyrase and engaged in interactions with crucial amino acid residues. In summary, our research underscores the efficacy of molecular hybridization in shaping the physicochemical, pharmacokinetic, and biological characteristics of novel indole-triazole derivatives.

Novel Fused Pyrimidines as Potent Cyclin-Dependent Kinases Inhibitor for Gastric Adenocarcinoma: Combined InVitro, In Silico Anticancer Studies.

Our research aims to design novel pyrimidine derivatives inspired by the common pyrimidine core found in many FDA-approved drugs. However, extensive prior research on the pyrimidine scaffold has made discovering new molecules more challenging. To overcome this obstacle, we employed a molecular hybridisation strategy, opting to hybridise tetralin and pyrimidine, recognising their potential in cancer therapeutics. The fused pyrimidine was synthesised through a base-mediated condensation of chalcone with amidine. The reaction conditions were further optimised for base, solvent, temperature and time to produce a series of 21 novel derivatives. These compounds were subsequently screened for anticancer activity against gastric adenocarcinoma cell lines using the MTT assay. Among the synthesised compounds, 2-(pyridin-3-yl)-4-(pyridin-3-yl)-5,6-dihydrobenzo[h]quinazoline 8b and 4-(2-(pyridin-3-yl)-5,6 dihydrobenzo[h]quinazolin-4-yl) phenol 5g exhibited potent anticancer activity compared to (R)-Roscovitine. Additionally, a molecular docking study was conducted to assess the reactivity of compound 5g, revealing that the presence of a phenolic hydroxyl group enables hydrogen bonding with CDKs and enhances anticancer activity. Furthermore, the efficacy of compound 5g was validated through an invitro CDK2/cyclin A2 enzyme inhibition assay. Interestingly, the observed CDK2 inhibitory activity showed a good correlation with the corresponding value for the antiproliferative activity of the tested compounds.

Design, synthesis, and in vitro and in vivo biological evaluation of dihydroartemisinin derivatives as potent anti-cancer agents with ferroptosis-inducing and apoptosis-activating properties

Natural products play a pivotal role in drug development, including their direct use as pharmaceuticals and their structural modification, yielding molecules with enhanced therapeutic potential. The discovery of bioactive molecules, lead compounds, and novel drugs is intrinsically linked to the structural optimization of natural products. In this study, forty-one derivatives of dihydroartemisinin (DHA) were synthesized by incorporating fragments with anti-tumour activity via molecular hybridization, and assessed for their anti-proliferative activity against human cancer cell lines (A549, Bel-7402, HCT-116, and SW620) and normal human liver cells (LO2). Most derivatives exhibited superior anti-proliferative activity compared to DHA. Notably, compound A3, featuring a 4-Cl phenyl carbamate moiety, demonstrated significant anti-proliferative activity against HCT-116 cells with an IC50 of 0.31 μM, making it 16-fold more potent than DHA (IC50 = 5.10 μM). The anti-proliferative mechanism did not involve cytotoxicity (SI = 54.13), indicating its superior safety profile compared to DHA (SI = 1.65).Further mechanistic studies revealed that compound A3 inhibits HCT-116 cell proliferation by modulating the expression of PI3K/AKT/mTOR and STAT3 proteins. STAT3 downregulation represses the expression of the critical ferroptosis protein glutathione peroxidase 4 (GPX4), aggravating the accumulation of reactive oxygen species (ROS) and depletion of glutathione (GSH). This redox imbalance triggers and accelerates ferroptosis. Additionally, A3 also induces apoptosis by damaging mitochondria and influencing MAPK signaling. Compound A3 arrested cells in the G2/M phase by regulating p53 expression. In an HCT-116 xenograft mouse model, compound A3 exhibited significant anti-cancer efficacy, with a tumor growth inhibition rate of 58.7 %. Therefore, compound A3 thus has the potential to serve as a lead compound for the development of new anti-tumor drugs.

11B NMR Together with Infrared Spectroscopy Provides Insight into Structural Elucidation of Quadrivalent Diazaborines & Cyclic Boronate Esters: Intriguing & Little-Explored.

Imidazo-fused diazaborines, which serve as intermediary structures somewhat alongside benzene and borazine, had been of particular interest to Dewar and Snyder more than 60 years ago. To this end, Dewar utilised his 'π-complex theory'so as to represent 'borazaros'as a 'quadrivalent' species; however, sadly, modern representations have deviated and leapt into 'trivalent' counterparts. Bonding in boron species has never been straightforward, to such an extent that the orthodox 'ethane' like diborane, i.e., H3B-BH3, which conformed to the paradigmatic rules of molecular structure, in particular, hybridisation and electronegativity, was later evolved to a more realistic '3-centre 2-electron' bonding so as to give the lie to the purported diborane structures of X-ray diffractors. Herein 11B NMR together with IR spectroscopy sheds light on the nature of bonding in borazaros, and 'caged' cyclic oxazaborons so as to reinforce, and reinvigorate the old literature, which could be of interest to both the synthetic, and medicinal chemist alike.

Exploring the Antitumor Potential of New Indazole-indolizines Designed by Molecular Hybridization

Background: Cancer represents the major health problem faced by the population of the world, remaining one of the main causes of death. Hence, the development of new targeted antitumor drugs with high efficacy and lower toxicity is still needed. Objective: As a continuation of our work to discover new molecules with cytotoxic properties, two heterocyclic scaffolds, namely indolizine, and indazole, were combined in the same molecule, aiming to improve the bioactivity. This article focused on the synthesis, characterization, and biological evaluation of a series of new indazole-indolizine hybrid compounds. Methods: The biological potential of the synthesized compound was investigated in vitro against the human farnesyltransferase enzyme and NCI 60 tumor cell lines panel. While the farnesyltransferase inhibitory activity was modest, a very good antiproliferative action was observed for compound 4a, which, at a concentration of 10 μM, inhibited the growth of 20 types of cancer cells by more than 50% and showed cytotoxic action against the ovarian cancer cell line OVCAR-4. Results: A series of novel indazole-indolizine hybrids were synthesized via a [3+2] cycloaddition reaction, fully characterized and biologically evaluated for antitumor potential. Conclusion: Compound 4a could be a promising starting point in the development of new antitumoral agents. Further biological investigations will be performed to identify the biological target of the compounds. Moreover, different synthetic strategies to introduce new substituents on the indolizine core will be addressed.

Ursolic Acid Conjugates: A New Frontier in Anticancer Drug Development.

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15 % of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18 c and 18 d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18 d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18 d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy.

Characterization of Changes in Ripening Process of Volatile Apple Compounds Based on HS-SPME-GC-MS Analysis

The aim of this study was to identify the aromatic compounds present in different apple varieties and to gain insights into the changes in the aromatic compounds during ripening. Three apple varieties (“Red Astrachan”, “Ning Qiu”, and “Golden Delicious”) at different stages of ripening were selected for this study; their peel and pulp were analyzed via headspace solid-phase microextraction (HS-SPME)–gas chromatography–mass spectrometry (HS-SPME-GC-MS), and 30 volatile compounds were identified. The samples’ differences were analyzed using heat map cluster analysis, principal component analysis (PCA), and an independent samples t-test. The results showed that the content of aromatic compounds in the peel was higher than that in the pulp. The relative content of esters in the aromatic compounds of the three apple varieties followed the order of pulp > peel and “Ning Qiu” > “Golden Delicious” > “Red Astrachan”. This suggests that “Ning Qiu” combines the advantages of its parents in terms of its aroma content. The highest concentrations of aroma compounds in “Red Astrachan” and “Ning Qiu” accumulate before the ripening stage, and care should be taken to choose an appropriate harvesting time according to the different needs during production. The main compounds of “Red Astrachan” are aldehydes and C8 esters, while those of “Ning Qiu” and “Golden Delicious” are alkenes and esters. After analyzing the relative odor activity values (rOAVs) of key volatile compounds and their aroma descriptors during the harvest period, acetic acid pentyl ester, butanoic acid hexyl ester, hexanoic acid hexyl ester, and 2-ethyl-1-Hexanol were found to contribute the most to the overall flavor of the peel and pulp. “Ning Qiu” combines the parental advantages of the concentrated peel of “Red Astrachan” and the astringent pulp of “Golden Delicious”, with compounds in its composition that give a pleasing aroma. Mature “Ning Qiu” fruits have a more intense aroma and fruity flavor. The development of flavor-specific varieties has provided the theoretical basis for future research in molecular hybridization, molecular-assisted breeding, and the molecular biology of apple flavor synthesis and metabolism.

Molecular docking, synthesis and preliminary evaluation of hybrid molecules of benzothiazole cross-linked with hydroxamic acid by certain linkers as HDAC inhibitors

Background Molecular hybridization in drug design is proved to be very successful approach to provide new chemical entities with potential activities and desirable physicochemical properties. Histone deacetylases (HDACs) are involved in controlling the behavior and acetylation of histone and non-histone proteins and their inhibition causes block of cell growth, differentiation, changes in gene expression, and death. Consequently, HDAC inhibitors may lead to anticytotoxic activity. An approach of synthesizing hybrid molecules of benzothiazole cross-linked with hydroxamic acid via an amino acid or aminoalkanoic acid was considered. This approach is expected to optimize the anticytotoxic activity of the proposed compounds. Methods Hybrid molecules of benzothiazole cross-linked with hydroxamic acid (2A-E) were synthesized and their chemical structures were confirmed by spectral analyses (FT-IR, 1H-NMR and 13C-NMR). These were subjected to molecular docking on HDAC8 (PDB ID: 1T69). Computational methods were employed using the SwissADME server to predict the ADME parameters and other physicochemical properties. The cytotoxicity evaluation was performed using MTT colorimetric assay. Results Hybrids (2A-E) recorded lower ΔG (-6.322 to - 9.46) than Vorinostat (SAHA, -5.375). ΔG is an affinity scoring function (kcal/mol) and is employed to rank the candidate poses as the sum of the electrostatic and Van der Waals energies. Benzothiazole cross-linked with hydroxamic acid by a p-aminobenzoic acid (2E) has recorded the lowest docking score of -9.460 and this may refer to the possibility of high inhibitory activity. The hybrids showed no violation from Lipinski’s rule and complied with parameters with low possible passive oral absorption and no penetration into BBB. Hybrid molecules of benzothiazole recorded very interesting results, particularly, 2D and 2E which showed significant and remarkable activity. Conclusions Hybrid molecules of benzothiazole cross-linked with hydroxamic acid recorded very interesting results, particularly, compounds 2D and 2E which showed significant and remarkable activity on lung cancer cell line type A549.

Isoniazid Hybrids As Potential Antitubercular Agents

AbstractThe rapid emergence of various forms of drug‐resistant tuberculosis (TB) has massively impacted people's health globally. According to the WHO, TB care and facilities have been downgraded by 21% since the COVID‐19 pandemic, which has further slowed down the progress toward the “End TB Strategy.” Multiple studies have shown drug‐resistant tuberculosis to be resilient to front‐line antituberculosis drugs, including isoniazid (INH), thus constantly prompting researchers worldwide to probe new potent chemical entities to replace/supplement the current artillery of anti‐TB therapeutics. The molecular hybridization (MH) technique has recently been adopted by many synthetic and medicinal chemists to combine different pharmacophoric units into a single molecular architecture which in most cases has been reported to exhibit a better pharmacological profile as compared to its precursors. The present review provides a concise account of the MH hybridization strategies directed at the structural manipulations of isoniazid to develop new anti‐TB agents and their structure‐activity relationships. Furthermore, their toxicity profiles and docking studies with relevant receptors are also briefly discussed.

New Quinazolinone‐Thiouracil Derivatives: Design, Synthesis, Anticancer Evaluation, and In Silico Analysis

AbstractQuinazolinone and thiouracil derivatives are key scaffolds in anticancer development. This study used a molecular hybridization approach to synthesize new quinazolinone‐thiouracil derivatives and evaluated their anticancer activity against three human cancer cell lines, namely breast, lung, and glioblastoma, using SRB assay. Structural elucidation was performed using IR spectroscopy, 1H‐NMR, 13C‐NMR, mass spectrometry, and elemental analysis. Most compounds show moderate to significant cytotoxic effects, with compound 5d displaying the highest potency (IC50 values of 5.28, 4.02, and 2.88 µM, respectively). Compound 5d also demonstrated comparable potency to positive controls cisplatin and temozolomide in lung and glioblastoma cancer cell lines and was nearly as effective as mitochondrial division inhibitor‐1 (mdivi‐1). Furthermore, molecular docking analyses revealed strong binding interactions of the synthesized compounds with dynamin‐related protein‐1 (drp1). Protein–ligand stability studies and all‐atom simulation confirmed the stable binding of compound 5d with drp1. In conclusion, this study identified compound 5d as a potent drp1 inhibitor and promising anticancer drug candidate, deserving further investigation.

Insight into the therapeutic potential of pyrazole-thiazole hybrids: A comprehensive review.

Several pyrazole-thiazole hybrids featuring two potentially bioactive pharmacophores with or without linker have been synthesized using the molecular hybridization approach as target structures by medicinal chemists to modulate multiple drug targets simultaneously. The presented review aims to provide an overview of the diversified and wide array of pharmacological activities of these hybrids bestowing anticancer, antifungal, antibacterial, analgesic, anti-inflammatory, antioxidant, antitubercular, antiviral, antiparasitic, and miscellaneous activities. The structure-activity relationships and potential mechanism of action are also reviewed to shed light on the development of more effective and biotargeted candidates. This review focuses on the latest research advances in the biological profile of pyrazole-thiazole hybrids reported from 2015 to the present, providing medicinal researchers with a comprehensive platform to rationally design and develop more promising pyrazole-thiazole hybrids.

A promising class of Antiprotozoal agents, design and synthesis of novel Pyrimidine–Cinnamoyl Hybrids

Malaria, caused by parasitic protozoans of the Plasmodium genus, continues to be one of the greatest global health crises, especially in Africa. The emergence of antimalarial drug resistance continues to be a health problem necessitating an urgent need for alternative and cost-effective antimalarials. Using a molecular hybridization approach, we report the design and synthesis of an efficacious novel class of antiprotozoal agents; (E)-1-(4-(4,6-diphenylpyrimidin-2-yl)piperazin-1-yl)-3-phenyl prop-2-en-1-one derivatives (8a-r). The in vitro inhibitory activity of the synthesized compounds was evaluated against the NF54 chloroquine-sensitive strain of Plasmodium falciparum. From the antiprotozoal screening, three compounds displayed propitious activity with IC50 values (0.18-0.21μM), using quinine and chloroquine as standard antimalarials. Compounds 8o and 8l emerged as the most potent candidates with IC50 values of 0.18 ± 0.02 μM and 0.21 ± 0.001 μM with an associated good safety index of 18.59 and 16.75 to human kidney epithelial (HEK293) cells, respectively. The synthesized analogues present a new chemical architecture structurally unrelated to the current regime of antimalarial drugs, representing a valid strategy to combat resistance in P. falciparum species to current commercial drugs. We further investigated the binding affinities of the compounds against recombinant forms of two P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, both of which are essential and promising druggable candidates. Compound 8l exhibited the highest binding affinity for both PfHsp70s. Furthermore, molecular docking revealed that compounds 8k, 8l, 8m, and 8o exhibited better fitness to PfHsp70-1, with compounds 8l and 8o showing the highest binding affinity of 10.5 kcal/mol and 10.1 kcal/mol, respectively. Therefore, it can be speculated that PfHsp70-1 may be a possible target of some of the inhibitors tested in this study. The presence of electron-donating groups on the phenyl ring of 4,6-pyrimidine moiety and cinnamoyl group demonstrated a positive correlation between the observed computational data and the biological activity. Taken together, this paper demonstrates the importance of using the molecular hybridization approach in the development of newer cinnamoyl clubbed with 4,6-diphenyl pyrimidine hybrids as potential antiprotozoal agents.

2‐Chloroquinolinyl‐thiazolidine‐2,4‐dione Hybrids as Potential α‐Amylase Inhibitors: Synthesis, Biological Evaluations, and In Silico Studies

AbstractRecently, molecular hybridization strategy has paved a way to develop novel lead compounds for the α‐amylase targeted antidiabetic therapy. In this study, we disclosed a series of new hybrids of thiazolidine‐2,4‐diones with 2‐chloroquinoline‐3‐yl moiety as potential antidiabetic agents. The molecular structures of all the synthesized hybrids (15a–n) were confirmed by spectroscopic studies (FT‐IR, ESI‐MS, 1H, 13C NMR, and elemental analysis). When in vitro antidiabetic evaluation of these agents was carried out in a dose‐dependent manner, it was revealed that several compounds (15f–h, 15j, and 15n) were endowed with significant antidiabetic activities and exhibited more than 50% α‐amylase inhibition at a dose of 50 µg/mL. Particularly, hybrid 15n was found to be more potent than acarbose with 95% inhibition of α‐amylase and IC50 of 5.00 ± 0.18 µM under given conditions. Further, it was demonstrated that 15n bearing 2‐chloroquinolinyl and thiazolidin‐2,4‐dione scaffolds functionalized with 3‐OMe and 4‐OH groups was not only able to effectively bind with α‐amylase receptor site with best docking score (−9.644 kcal/mol) but also possessed drug‐likenesses properties with no violations of Lipinski rule. Overall, this study discovered new 2‐chloroquinolinyl‐thiazolidine‐2,4‐diones hybrids as novel α‐amylase inhibitors and compound 15n as promising lead for its further development as antidiabetic agent.

Design, synthesis and antitumor activity of novel 4-oxobutanamide derivatives

To find highly effective and low-toxicity antitumor drugs to overcome the challenge of cancer, we designed and synthesized a series of novel 4-oxobutanamide derivatives using the principle of molecular hybridization and tested the antiproliferative ability of the title compounds against human cervical carcinoma cells (HeLa), human breast carcinoma cells (MDA-MB-231) and human kidney carcinoma cells (A498). Among them, N1-(4-methoxybenzyl)-N4-(4-methoxyphenyl)-N1-(3,4,5-trimethoxyphenyl) succinimide DN4 (IC50 = 1.94 µM) showed the best proliferation activity on A498, superior to the positive control paclitaxel (IC50 = 8.81 µM) and colchicine (IC50 = 7.17 µM). Compound DN4 not only inhibited the proliferation, adhesion and invasion of A498, but also inhibited angiogenesis and tumor growth in a dose-dependent manner in the xenograft model of A498 cells. In addition, we also predicted the physicochemical properties and toxicity (ADMET) of these derivatives, and the results suggested that these derivatives may have the absorption, distribution, metabolism, excretion, and toxicity properties of drug candidates. Thus, compound DN4 may be a promising drug candidate for the treatment of cancer.

Design, synthesis and biological evaluation of novel curcumin-fluorouracil hybrids as potential anti-cancer agents

The latest global cancer data statistics report shows that cancer poses a serious threat to human life and health; The number of new cancer and death cases worldwide is severe. Molecular hybridization is considered an effective strategy for developing new anti-cancer drugs. Curcumin (Cur) is a natural active compound containing Michael receptors that target thioredoxin reductase (TrxR). Fluorouracil (5-FU) is the first anti-metabolic drug synthesized based on certain assumptions for tumor treatment, acting on thymidylate synthase (TS). This study synthesized a series of novel hybrid derivatives of Cur and 5-FU, and evaluated their anti-tumor cell proliferation effects. Several compounds with good cytotoxic activity against tumor cells were discovered; and they exhibited high selectivity towards A549 cells, compared to normal THLE cells. Among them, the hybrid derivative F-4 has the best anti-proliferative activity in tumor cells. F-4 can target TrxR, increase reactive oxygen species levels in tumor cells, and lead to tumor cell apoptosis, which may be related to the Michael receptor structure in the chemical structure of F-4; F-4 can also target TS, leading to cell cycle arrest in G0/G1 phase, which may be related to the 5-FU structure in the chemical structure of F-4. Moreover, F-4 can effectively exert anti-tumor activity in mice, significantly reduce tumor volume and weight, and has low toxic side effects. These results indicate that Cur-5-FU hybrid derivative F-4 is a novel lead compound with in vivo anti-tumor activity and minimal side effects, which deserves further investigation.

Carvacrol-conjugated 3-Hydroxybenzoic Acids: Design, Synthesis, cardioprotective potential against doxorubicin-induced Cardiotoxicity, and ADMET study

Carvacrol (CA) is a phenolic monoterpene renowned for its diverse pharmacological benefits, particularly its cardioprotective effects. Concurrently, phenolic acids have also demonstrated promise in mitigating drug-induced cardiotoxicity. Focusing on combating doxorubicin-induced cardiotoxicity (DIC), the research aims to synthesize novel cardioprotective agents by combining CA with 3-hydroxybenzoic acid (3HA). Doxorubicin, an anticancer drug, poses cardiovascular risks as its adverse effect, prompting the exploration of hybrid compounds. Various linker molecules, including alkyl and acyl with different carbon lengths, were investigated to understand their impact on bioactivity. In vitro testing on the DOX-induced H9c2 cell death model revealed the effectiveness of a CA conjugate in preserving cardiomyocyte viability. In silico analysis highlighted favorable drug-like properties and low toxicity of the conjugate. This study sheds light on molecular hybridization’s potential in developing cardioprotective agents, emphasizing CA’s pivotal role in combating DIC.

Clinical informatics and molecular hybridization of established clinical DPP-4 inhibitors to generate next-level diabetes type 2 drugs

Clinical informatics and molecular hybridization of established clinical DPP-4 inhibitors to generate next-level diabetes type 2 drugs

Microwave-assisted synthesis of indoloquinoxaline derivatives as promising anti-alzheimer agents: DFT and molecular docking study

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. One of the major pathological features of AD is the degeneration of cholinergic neurons and associated loss of acetylcholine (ACh), a key neurotransmitter involved in memory and cognition. Reduced ACh levels correlate with the severity of cognitive symptoms in AD. Thus, inhibition of acetylcholinesterase (AChE), the enzyme responsible for breaking down ACh, is a leading treatment strategy. This study aimed to synthesize and evaluate novel AChE inhibitors based on an indolo[2,3-b]quinoxaline scaffold. A series of indolo[2,3-b]quinoxaline derivatives were designed by molecular hybridization of indole and quinoxaline privileged structures. Microwave-assisted synthesis improved the efficiency of obtaining the desired compounds. In vitro screening identified several potent AChE inhibitors, with IC50 values down to 0.02 µM. The most active compounds contained electron-withdrawing groups like nitro and benzoyl moieties. DFT calculations provided insights into geometrical, thermal, and electronic properties of the compounds. FMO analysis revealed variations in HOMO and LUMO energies that impact reactivity. Molecular docking elucidated binding modes, highlighting the pi-pi, pi-H, and H-bonding interactions with key amino acids in the catalytic gorge of AChE. Overall, the indole-quinoxaline hybrids represent promising candidates for development of novel dual binding site AChE inhibitors and multifunctional anti-Alzheimer agents.

Oxindole–benzothiazole hybrids as CDK2 inhibitors and anticancer agents: design, synthesis and biological evaluation

In the current study, molecular hybridization between the oxindole core and benzothiazole system through an acetohydrazide moiety was accomplished for the design of a new series of oxindole–benzothiazole hybrids 9a–r targeting CDK2 for cancer therapy. The afforded hybrids displayed promising growth inhibitory activity on NCI cancer cell lines at 10 µM. Compound 9o displayed mean GI% = 55.91%. Based on the potent activity of 9o, it was further assessed for its cytotoxic activity at five dose level and it demonstrated GI50 reaching 2.02 µM. Analysis of the cell cycle of the prostate cancer cell line DU145 after treatment with 9o confirmed its ability to arrest its cell cycle at the G1 phase. Moreover, 9o proved its ability to potentiate the apoptosis and necrosis of the same cell line. Furthermore, the oxindole–benzothiazole hybrids 9b, 9f and 9o showed IC50 = 0.70, 0.20 and 0.21 µM, respectively on CDK2. Besides, molecular docking simulation of the synthesized oxindole–benzothiazole hybrid 9o proved the expected binding mode which involves the accommodation of the oxindole moiety in the ATP binding pocket where it is involved in hydrogen bonding and hydrophobic interactions with the essential amino acids in the hinge region while the benzothiazole moiety is oriented toward the solvent region. Investigation of the physicochemical properties of the hybrids 9a–r highlights their acceptable ADME properties that can be somewhat developed for the discovery of new anticancer agents.