Compound 5a Research Articles

Synthesis, Identification, and Docking Study of Novel Derivatives of Aziridine

Aziridines are three-membered ring heterocycles that include nitrogen and are well-known for their employment as reactive intermediates in the production of chiral amino alcohols, azomethine ylides, and derivatives of amino acids. The current study was based on the synthesis, identification, docking study and evaluation of antioxidant potential of novel derivatives of aziridine. The novel derivatives of aziridine were synthesized and identified the synthesized aziridine derivatives based on physicochemical properties i.e., boiling point, Rf value, FTIR, NMR and Mass spectroscopy and Docking study. With a binding energy of -6 to -9 Kcal/mol, every chemical has demonstrated effective docking inside the antioxidant activity protein's active region. We contrasted the anticipated docking data with proteins known to have antioxidant action. In results, the % yield was observed as 48.24, 49.72, 48.39 and 49.12 in compound A4, A7, A10 and A12, respectively. Highest Rf values were observed in A3, A5, A7 and A 11 as 0.74, 0.76, 0.77, and 0.74, respectively. A4 showed boiling point 210ºC. Based on docking study, all the compounds were found active, however compound A1, and A4 were demonstrated the highest binding energy (affinity). Derivatives of aziridine A2, A3, A5, A6, A8, A9, A10, A11, A12 were found also found active with some moderate binding affinity. It concluded that 12 novel derivatives of aziridine were synthesized and characterized with their physicochemical properties and spectral analysis (NMR, Mass, FTIR). In docking study, compounds A1 and A4 demonstrated the highest binding affinity among all 12 aziridine derivatives. Thus, active aziridine derivatives might be used in the evaluation of the biological potential. It suggests to perform the acute oral toxicity of the synthesized aziridine derivatives and antioxidant activity.

New heterocycles from dehydroacetic acid (DHA). Synthesis, antimicrobial activity, DNA gyrase inhibition, antioxidant activity, and molecular docking study

Dehydroacetic acid (DHA) is a significant heterocyclic molecule whose derivatives are highly prevalent. Thus, a new series of heterocyclic derivatives starting from dehydroacetic acid were synthesized and investigated for their antimicrobial and antioxidant activities. The antimicrobial activity of the twenty-one new compounds was determined against S. aureus ATCC 6538-P, E. coli ATCC 25922, C. albicans ATCC 10231, and A. niger NRRL A-326. Out of twenty one compounds, 7a, 8a, 9, 10d and 14 showed promising in vitro antimicrobial activity. Compounds 7a, 8a, and 10d were equipotent to ciprofloxacin reference drug against S. aureus, while compounds 9 and 14 were 4-fold and 2-fold higher than ciprofloxacin, respectively. For E. coli, compounds 9 and 10d were equipotent to ciprofloxacin whereas compounds 7a, 8a, and 14 were 4-fold, 8-fold, and 2-fold higher than ciprofloxacin, respectively. Regarding C. albicans,7a showed moderate activity with 2-fold lower than nystatin (reference drug). To further analyze the antimicrobial potential of the compounds (7a, 8a, 9, 10d, and 14), their in vitro inhibitory activity against E. coli DNA gyrase was evaluated. The results revealed that compound 8a showed the lowest IC50 required for DNA gyrase inhibition almost similar IC50 to ciprofloxacin. A molecular docking study was established to assess the binding mode of 8a, the most active derivative, with the crystal structure of DNA gyrase B (PDB: 5MMN). 8a demonstrated a good binding mode inside the active pocket of the DNA gyrase B with good binding energy value. Additionally, 8a displayed the highest antioxidant activity compared with ascorbic acid. Collectively, the compound 8a is a highly promising antimicrobial candidate for further studies.

Aggregation-Induced Emission Enhancement and Solid-State Photoswitching of Crystalline Carbazole N-Salicylidene Anilines.

The development of fluorescent stimuli-responsive organic materials has attracted substantial interest due to their increasing optoelectronic applications. This study systematically introduces fluorine atoms on one end of carbazole-based N-salicylidene anilines 5a-5f to elucidate the impact in their solution and solid-state photophysics. The addition of fluorine atoms at one end of the molecule induced significant changes, for example, a reduction in the quantum yield (QY) fluorescence emission in solution, going from QY near unity in compound 5a (QY ∼ 100%) to a negligible emission in 5f (QY < 1%). Similarly, compound 5a showed a very strong aggregation-induced enhancement emission behavior, whereas compounds with a higher fluorine content were almost quenched. Furthermore, the crystalline solid-state photoisomerization in N-salicylidene anilines is not trivial, and only compounds with three (5e) and five fluorine atoms (5f) exhibited reversible solid-state photoisomerization under 405 nm light source irradiation. We propose that the presence of the arene-perfluoroarene interaction in the crystalline array facilitates the latter behavior. Our findings present a comprehensive study of crystal engineering for the obtention of photoswitchable crystalline materials and adjustable photophysics response, paving the way for its implementation in other systems.

Structure-guided Development of Novel Benzothiophene Derivatives as PLK1-PBD Inhibitors

Background: Polo-like kinase 1 (PLK1), a validated target for tumor therapy, plays a key role in mitosis and is over-expressed in many tumors. In addition to its N-terminal kinase domain, PLk1 also harbors a C-terminal polo-box domain (PBD). Objective: A candidate based on PLK1-PBD was developed as a promising compound for future development. Methods: Seventeen small molecule PLK1-PBD inhibitors were designed, synthesized and evaluated for PLK1-PBD inhibitory activities by fluorescence polarization (FP) assay. The compounds with better inhibitory activities were further assessed for their anti-proliferative activities using a CCK-8 method. Results: The inhibitory rates of compounds 7a, 7d, 14a, 14d, 14e and 14f exceeded 98%. The IC50 values of compounds 7d, 14d, 14e, and 14f were 0.73 μM, 0.67 μM, 0.89 μM and 0.26 μM, proving better than MCC1019. Compound 14f showed the best inhibitory activity (IC50: 0.26 μM) and antiproliferative activities against three cancer cell lines (HeLa, HepG2 and MG63). Especially, compound 14f also exhibited acceptable safety profiles in the human ether-a-go-go related gene (hERG) and normal cell tests. The results of docking and prediction studies indicated that compound 14f had a high binding affinity to the target, with good drug-like absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Conclusion: Compound 14f can be a promising compound for future development.

Deciphering the cytotoxic and antioxidant potential of 3,5-disubstituted isoxazole-linked benzimidazolone derivatives

A series of new isoxazole derivatives containing a benzimidazolone has been synthesized by cycloaddition reaction using various nitrile oxides. In all cases, these cycloadditions are completely chemo and regioselective. The structures of the new cycloadducts were characterized by 1H, 13C NMR spectroscopy, HRMS and confirmed in one case by a single crystal structure determination. The isoxazole compounds were evaluated for in vitro antioxidant activity using the DPPH and ABTS methods. As a result, compound 5a showed good antioxidant activity. The results of the acute toxicity study of the heterocycles studied by the oral route showed no deaths and no clinical signs of toxicity. Additionally, the Hirshfeld surface analysis and the molecular electrostatic potential using density functional theory (DFT) modeling at the B3LYP/6–31G(d,p) level. Hirshfeld surface analysis (dnorm surface and 2D-fingerprint plots) revealed the nature of intermolecular contacts. H⋯H interactions make the most significant contribution to crystal packing. The optimized structural parameters obtained through DFT calculations closely matched those determined via X-ray analysis, demonstrating strong agreement between theoretical predictions and experimental observations.

Exploring novel A2AAR antagonists: Design, synthesis, and evaluation of 2,6,9-trisubstituted purine derivatives as promising antifibrotic agents

A series of 2,6,9-trisubstituted purine derivatives were designed and synthesized with diverse chemical moieties. Through a comprehensive biological evaluation, we identified 4-(6-(methylamino)-2-(phenylethynyl)-9H-purin-9-yl)phenol (6a) as a promising A2AAR antagonist with potent antifibrotic properties. Compound 6a demonstrated significant efficacy in inhibiting CRE promoter activity and in reducing the expression of fibrogenic marker proteins and downstream effectors of A2AAR activation, surpassing the A2AAR antagonist ZM241385 and initial screening hits, 9-benzyl-N-methyl-2-(phenylethynyl)-9H-purin-6-amine (5a) and 9-((benzyloxy)methyl)-N-methyl-2-(phenylethynyl)-9H-purin-6-amine (5j). Further validation revealed that compound 6a effectively inhibited fibrogenic marker proteins induced by A2AAR overexpression or TGF-β1 treatment in hepatic stellate cells, alongside reducing PKA and CREB phosphorylation. These findings suggest that compound 6a exerts its antifibrotic action by modulating the cAMP/PKA/CREB pathway through A2AAR inhibition. Overall, our study provides valuable insights for the development of novel therapeutics that target hepatic fibrosis through A2AAR antagonism.

Pyridazinone-based derivatives as anticancer agents endowed with anti-microbial activity: molecular design, synthesis, and biological investigation.

Cancer patients undergoing chemotherapy are highly susceptible to infections owing to their compromised immune system, which also promotes cancer progression through inflammation. Thus, this study aimed to develop novel chemotherapeutic agents with both anticancer and antimicrobial properties. A series of diarylurea derivatives based on pyridazinone scaffolds were designed, synthesized, and characterized as surrogates for sorafenib. The synthesized compounds were tested for their antimicrobial activity and screened against 60 cancer cell lines at the National Cancer Institute (NCI). Compound 10h exhibited potent antibacterial activity against Staphylococcus aureus (MIC = 16 μg mL-1), whereas compound 8g showed significant antifungal activity against Candida albicans (MIC = 16 μg mL-1). Additionally, ten compounds were further evaluated for VEGFR-2 inhibition, with compound 17a showing the best inhibitory activity. Compounds 8f, 10l, and 17a demonstrated significant anticancer activity against melanoma, NSCLC, prostate cancer, and colon cancer, with growth inhibition percentages (GI%) ranging from 62.21% to 100.14%. Compounds 10l and 17a were selected for five-dose screening, displaying GI50 values of 1.66-100 μM. Compound 10l induced G0-G1 phase cell cycle arrest in the A549/ATCC cell line, increasing the cell population from 85.41% to 90.86%. Gene expression analysis showed that compound 10l upregulated pro-apoptotic genes p53 and Bax and downregulated the anti-apoptotic gene Bcl-2. Molecular docking studies provided insights into the binding modes of the compounds to the VEGFR-2 enzyme. In conclusion, the pyridazinone-based diarylurea derivatives developed in this study show promise as dual-function antimicrobial and anticancer agents, warranting further investigation.

Halogenated retinoid derivatives as dual RARα and RXRα modulators for treating acute promyelocytic leukemia cells

Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα′s tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G2/M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.

Design, Synthesis, and Biological and in silico Evaluation of Novel Indazole-pyridine Hybrids for the Treatment of Breast Cancer.

The prevalence of breast cancer presents a substantial global health concern, underscoring the ongoing need for the development of inventive therapeutic remedies. In this investigation, an array of novel indazole-pyridine hybrids (5a-h) have been designed and synthesized to assess their potential as candidates for treating breast cancer. Subsequently, we have conducted biological evaluations to determine their cytotoxic effects on the human MCF-7 breast cancer cell line. Furthermore, in silico analysis was conducted to estimate the inhibition potential of the compounds against TrkA (Tropomyosin receptor kinase A), a specific molecular target associated with breast cancer, through molecular docking. In silico physicochemical and pharmacokinetic predictions were made to assess the compounds' drug-like properties. Compound 5a emerged as the most active compound among the others with GI50 < 10 μg/ml. Besides, compound 5a showed high binding energy (BE -10.7 kcal/mol) against TrkA and was stabilized within the TrkA binding pocket through hydrophobic, H-bonding, and van der Waals interactions. In silico physicochemical and pharmacokinetic prediction studies indicated that compound 5a obeyed both Lipinski's and Veber's rule and displayed a versatile pharmacokinetic profile, implying compound 5a to appear as a viable candidate and that it could be further refined to develop therapeutic agents for potentially treating breast cancer. This study offers a promising direction for the advancement of innovative breast cancer treatments, highlighting the effectiveness of indazole-pyridine hybrids as potential anticancer agents. Further optimization and preclinical development are necessary to advance these compounds to clinical trials.

Rational design, synthesis, and anti-cancer evaluation of amide derivatives of 1,3,4-Thiadiazole benzimidazoles

A series of amide derivatives of 1,3,4-thiadiazole-benzimidazole (13a-j) has been designed, synthesized and screened for their anticancer activities against human breast cancer cell line (MCF-7), human lung cancer (A549), human colon cancer (Colo-205) & human ovarian cancer (A2780) by employing of MTT method with Etoposide as standard drug. Among the synthesized derivatives, the compound 13a with electron donating 3,4,5-trimethoxy substituent showed potent anticancer activity (MCF-7 = 0.04 ± 0.008 µM; A549 = 0.06 ± 0.009 µM; Colo-205 = 0.12 ± 0.067 µM & A2780 = 0.19 ± 0.071 µM. The compound 13a, shown two H-bonding contacts with PHE106, TYR 67 amino acids are O and NH group, as well as with additional hydrophobic interactions, including − stacking with aromatic rings and also had a binding affinity of −12.04 kcal/mole.

Synthesis of New Glucose-containing 5-Arylisoxazoles and their Enzyme Inhibitory Activity

Abstract: Carbohydrates are an important group of biomolecules that have received special attention due to their significant role in the design and synthesis of new bioactive compounds. In this study, a new class of 5-arylisoxazole-glucose hybrids was designed and synthesized for evaluation of their inhibitory effects on α-glucosidase, α-amylase, and tyrosinase. The target compounds depicted selective α-glucosidase inhibitory activity over α-amylase, which is an important factor in reducing probable gastrointestinal problems in the treatment of type 2 diabetes. In this respect, compound 9a, possessing the phenylisoxazole group, was found to be the most potent α-glucosidase inhibitor (IC50 = 292.2 ± 0.1 μM) compared to acarbose (IC50 = 750.2 ± 0.1 μM) as the positive control. All compounds were also evaluated for their anti-tyrosinase effect, and among them, compound 9j, containing a fluoroaryl moiety, showed potent activity (IC50 = 50.1 ± 6.3 μM) in comparison to kojic acid (IC50 = 23.6 ± 2.6 μM). Also, docking studies were performed to investigate the probable mode of action, which indicated the construction of important H-bonding interactions between the sugar moiety and the enzyme’s active sites. According to the results, hybrids containing heterocycles attached to glucose can be used to inhibit α-glucosidase.

Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening

Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a, a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC50 = 0.24 μmol/L). Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.

Cholesterol-based mesogenic Schiff’s base derivatives: Biological evaluation, photoluminescence and DFT studies

This study presents the synthesis and comprehensive characterization of novel thiazole Schiff’s base compound linked to various substituted formylphenyl cholesteryl carbonates. The structures were confirmed by elemental analysis and 1H NMR, 13C NMR, and FT-IR spectroscopy. Optical texture investigations revealed that only compound 7a exhibited liquid crystalline behaviour, specifically showing a chiral nematic (N*) mesophase. Thermal properties were analyzed using differential scanning calorimetry (DSC) showing phase transitions, and thermogravimetric analysis (TGA) indicating their stability ranging from 223 to 361 °C. The compound 7a exhibited significant antibacterial activity with zone of inhibition of 18 mm for Staphylococcus aureus (gram-positive) and 25.5 mm for Escherichia coli (gram-negative), and compound 7a and 8 displayed highest antifungal activity with zone of inhibition of 17.5 mm and 24.5 mm against Aspergillus niger and Candida albicans, respectively. Antioxidant activity was assessed using the DPPH assay, where compound 8 showed superior scavenging activity with IC50 value of 101.32 µg/mL. Additionally, the compounds were UV-active and exhibited photoluminescence, showing emission peaks ranging from 412 to 434 nm and a quantum yield of 0.11 to 0.23. In silico predictions indicated promising drug-likeness and bioactivity scores. Density Functional Theory (DFT) calculations provided insights into the electronic properties and molecular interactions. This research highlights the potential of these thiazole Schiff base derivatives for applications in pharmaceuticals and materials science, contributing valuable data on their multifunctional properties.

Design, synthesis, and biological evaluation of β-carboline-cinnamic acid derivatives as DYRK1A inhibitors in the treatment of diabetes

Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote β cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series β-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet β cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet β cell proliferation at a concentration of 1 μM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that β-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic β cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes.

Ligand-Based Pharmacophoric Design and Anti-inflammatory Evaluation of Triazole Linked Semisynthetic Labdane Conjugates.

This study employed a ligand-based pharmacophoric approach to design and synthesize 33 novel semisynthetic labdane-appended triazolyl isatins to discover potential anti-inflammatory agents. The anti-inflammatory efficacy of the derivatives was evaluated by their ability to inhibit the production of NO, TNF-α, and IL-6, in lipopolysaccharide-induced RAW264.7 macrophages. The initial screening revealed that compound 7a ((1-(2-(2,3-dioxoindolin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl (E)-3-formyl-5-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)pent-3-enoate) exhibited an anti-inflammatory effect (NO inhibition, IC50 = 3.13 μΜ), surpassing both the positive control indomethacin (NO inhibition, IC50 = 7.31 μΜ) and the parent compound labdane dialdehyde. Notably, 7a reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 while increasing the levels of the anti-inflammatory cytokine IL-10. Mechanistic studies revealed that 7a downregulated the expression of COX-2 and iNOS by inhibiting the NF-κB signaling pathway. In silico molecular modeling studies on NF-κB proteins support these findings, suggesting that 7a is a promising candidate for developing into a potent anti-inflammatory clinical agent.

Development of non-acidic 4-methylbenzenesulfonate-based aldose reductase inhibitors; Design, Synthesis, Biological evaluation and in-silico studies

Design and virtual screening of a set of non-acidic 4-methyl-4-phenyl-benzenesulfonate-based aldose reductase 2 inhibitors had been developed followed by chemical synthesis. Based on the results, the synthesized compounds 2, 4a,b, 7a-c, 9a-c, 10a-c, 11b,c and 14a-c inhibited the ALR2 enzymatic activity in a submicromolar range (99.29–417 nM) and among them, the derivatives 2, 9b, 10a and 14b were able to inhibit ALR2 by IC50 of 160.40, 165.20, 99.29 and 120.6 nM, respectively. Moreover, kinetic analyses using Lineweaver–Burk plot revealed that the most active candidate 10a inhibited ALR2 potently via a non-competitive mechanism. In vivo studies showed that 10 mg/kg of compound 10a significantly lowered blood glucose levels in alloxan-induced diabetic mice by 46.10 %. Moreover, compound 10a showed no toxicity up to a concentration of 50 mg/kg and had no adverse effects on liver and kidney functions. It significantly increased levels of GSH and SOD while decreasing MDA levels, thereby mitigating oxidative stress associated with diabetes and potentially attenuating diabetic complications. Furthermore, the binding mode of compound 10a was confirmed through MD simulation. Noteworthy, compounds 2 and 14b showed moderate antimicrobial activity against the two fungi Aspergillus fumigatus and Aspergillus niger. Finally, we report the thiazole derivative 10a as a new promising non-acidic aldose reductase inhibitor that may be beneficial in treating diabetic complications.

Chiral thioureas containing naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, cholinesterase inhibition activity and molecular docking studies

Butyrylcholinesterase (BChE), which plays a role in the regulation of acetylcholine (ACh) as well as cholinergic type neurotransmission, also has non-cholinergic functions such as differentiation, proliferation and apoptosis. The strategy of increasing ACh levels without the typical undesirable effects of AChE inhibitors used in treatment with selective inhibition of BChE may be an effective approach to delay the progression of Alzheimer's disease (AD). Based on this approach, twenty derivatives of chiral thioureas containing the naphthalene moiety (1a-10a and 1b-10b) in both enantiomeric forms were designed, synthesized with good yields (up to 90 %), in this study. Also, their AChE and BChE inhibition activities and antioxidant profiles were tested. All chiral thioureas except compound 5b showed excellent inhibitory activity against BChE but lower inhibitory activity against AChE compared to galantamine. The activity results on BChE revealed that compound 1b (S-enantiomer) had the strongest inhibitory effect on BChE (IC50 = 10.18 ± 1.02 μM) with a selectivity index of 7.27 among all compounds. In terms of antioxidant activity, compound 7a (R-isomer) exhibited the overall highest antioxidant profile in the series of chiral thioureas. Molecular docking studies were used to reveal the interactions of the most active compounds with target enzymes. Besides, an estimation of the drug-likeness and pharmacokinetic properties of all chiral thioureas was performed.

Design, synthesis and biological activity evaluation of eco-friendly rosin-based fungicides for sustainable crop protection.

Utilizing fungicides to protect crops from diseases is an effective method, and novel eco-friendly plant-derived fungicides with high efficiency and low toxicity are urgent requirements for sustainable crop protection. Two series of rosin-based fungicides (totally 35) were designed and synthesized. In vitro fungicidal activity revealed that Compound 6a (Co. 6a) effectively inhibited the growth of Valsa mali [median effective concentration (EC50) = 0.627 μg mL-1], and in vivo fungicidal activity suggested a significant protective efficacy of Co. 6a in protecting both apple branches (35.12% to 75.20%) and apples (75.86% to 90.82%). Quantum chemical calculations (via density functional theory) results indicated that the primary active site of Co. 6a lies in its amide structure. Mycelial morphology and physiology were investigated to elucidate the mode-of-action of Co. 6a, and suggested that Co. 6a produced significant cell membrane damage, accelerated electrolyte leakage, decreased succinate dehydrogenase (SDH) protein activity, and impaired physiological and biochemical functions, culminating in mycelial mortality. Molecular docking analysis revealed a robust binding energy (ΔE = -7.29 kcal mol-1) between Co. 6a and SDH. Subsequently, biosafety evaluations confirmed the environmentally-friendly nature of Co. 6a via the zebrafish model, yet toxicological results indicated that Co. 6a at median lethal concentration [LC50(96)] damaged the gills, liver and intestines of zebrafish. The above research offers a theoretical foundation for exploiting eco-friendly rosin-based fungicidal candidates in sustainable crop protection. © 2024 Society of Chemical Industry.

Design, synthesis, and biological activity evaluation of novel HDAC3 selective inhibitors for combination with Venetoclax against acute myeloid leukemia

Histone deacetylases (HDACs) are highly attractive targets in the drug development process, and the development of subtype-selective HDAC inhibitors is the research direction for HDAC inhibitors. As an important member of the HDAC family, HDAC3 has been found to be closely related to the pathological progression of many diseases due to its abnormal expression. In previous studies, we discovered compound 13a, which has potent inhibitory activity against HDAC1, 2, and 3. In this work, we improved the HDAC3 isotype selectivity of 13a, and obtained compound 9c through rational drug design. 9c shows a selectivity of 71 fold for HDAC3 over HDAC1 and can significantly inhibit the proliferation activity of MV4-11 cells in vitro. Furthermore, when combined with Venetoclax, 9c can effectively induce apoptosis in MV4-11 cells in vitro and reduce the expression of anti-apoptotic proteins, the development of HDAC3 selective inhibitors may serve as a potential lead compound to reverse Venetoclax resistance.

Novel Coumarin-Nucleobase Hybrids with Potential Anticancer Activity: Synthesis, In Vitro Cell-Based Evaluation, and Molecular Docking.

A new series of compounds planned by molecular hybridization of the nucleobases uracil and thymine, or the xanthine theobromine, with coumarins, and linked through 1,2,3-triazole heterocycles were evaluated for their in vitro anticancer activity against the human tumor cell lines: colon carcinoma (HCT116), laryngeal tumor cells (Hep-2), and lung carcinoma cells (A549). The hybrid compound 9a exhibited better activity in the series, showing an IC50 of 24.19 ± 1.39 μM against the HCT116 cells, with a selectivity index (SI) of 6, when compared to the cytotoxicity against the non-tumor cell line HaCat. The in silico search for pharmacological targets was achieved through molecular docking studies on all active compounds, which suggested that the synthesized compounds possess a high affinity to the Topoisomerase 1-DNA complex, supporting their antitumor activity. The in silico toxicity prediction studies suggest that the compounds present a low risk of causing theoretical mutagenic and tumorigenic effects. These findings indicate that molecular hybridization from natural derivative molecules is an interesting approach to seek new antitumor candidates.