Potent Compounds Research Articles

Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives.

The present structure-activity relationship study investigates the development of novel chemosensitizers targeting therapy-resistant cancer stem cells (CSCs). We used 4'-((2-propyl-1H-benzo[d]imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from the angiotensin II type 1 receptor blocker telmisartan, as a lead structure, demonstrating that the biphenyl moiety is essential for chemosensitizing activity. Introducing a methyl carboxylate or carboxamide instead of the COOH-group significantly enhanced this effect, leading to the development of highly potent compounds. These novel, noncytotoxic chemosensitizers effectively target CSCs and overcome drug resistance by interfering with CSC persistence mechanisms─hyperactivated STAT5 signaling and increased drug transporter activity─with demonstrated efficacy in leukemia, ovarian, and prostate cancers. The carboxamide of telmisartan (telmi-amide, 7c) significantly reduced tumor growth in an imatinib-resistant leukemia xenograft model, both as monotherapy and combined with imatinib, showing promising oral bioavailability and tolerability. In summary, telmisartan derivatives act as effective chemosensitizers and offer an innovative strategy for targeting CSCs in various malignant diseases.

Comprehensive Biotechnological Strategies for Podophyllotoxin Production from Plant and Microbial Sources.

Podophyllotoxin is derived from plant sources and exhibits strong anticancer activity. However, limited natural availability and environmental impacts from traditional extraction methods drive the search for alternative production approaches. This review explores diverse strategies for sustainable podophyllotoxin synthesis, including biosynthesis, semi-synthesis, and biotransformation. Biosynthetic methods involve metabolic pathway engineering in plant or microbial cells, enabling increased yields by manipulating precursor availability and gene expression. Semi-synthetic approaches modify podophyllotoxin precursors or intermediates to enhance therapeutic effects, with derivatives like etoposide and teniposide showing clinical efficacy. Biotransformation, utilizing organisms such as endophytic fungi or human hepatic enzymes, enables the transformation of substrates like deoxypodophyllotoxin into podophyllotoxin or its derivatives, yielding compounds with reduced environmental impact and improved purity. The anticancer efficacy of podophyllotoxin and its derivatives stems from multiple mechanisms. These compounds disrupt cell mitosis by inhibiting microtubule assembly, impairing nucleoside transport, and blocking topoisomerase II activity, leading to DNA cleavage and cancer cell apoptosis. Podophyllotoxin and its derivatives also exhibit anti-angiogenesis and anti-metastatic effects through signalling pathway modulation. Notably, derivatives like deoxypodophyllotoxin utilize advanced delivery systems, enhancing targeted efficacy and reducing side effects. Given the varied mechanisms and growing therapeutic applications, optimizing biotransformation and delivery techniques remains essential for advancing podophyllotoxin-based therapies. This comprehensive review underscores the compound's potential as a robust anticancer agent and the need for continued research to maximize its production and clinical effectiveness.

Structure-based virtual screening of Trachyspermum ammi metabolites targeting acetylcholinesterase for Alzheimer's disease treatment.

In recent decades, Alzheimer's disease (AD) has garnered significant attention due to its rapid global prevalence. The cholinergic hypothesis posits that the degradation of acetylcholine by acetylcholinesterase (AChE) contributes to AD development. Despite existing anti-AChE drugs, their adverse side effects necessitate new agents. This study analyzed 150 bioactive phytochemicals from Trachyspermum ammi using structure-based drug design and various in-silico tools to identify potent anti-AChE compounds. Compounds were screened for drug-likeness (QEDw ≥50%) and bioavailability (≥55%) and underwent toxicity profiling via the ProTox-II server. Selected compounds were prepared for molecular docking with the human AChE protein as the receptor. Viridifloral, 2-Methyl-3-glucosyloxy-5-isopropyl phenol, Alpha-Curcumene, and Sterol emerged as top candidates with high AChE affinity. These results were validated by molecular dynamics simulations, confirming stable interactions. The hit compounds were further evaluated for drug-likeness using Lipinski's rule and ADMET properties, confirming favorable pharmacokinetic profiles. DFT optimization analyzed frontier molecular orbitals and electrostatic potential, demonstrating favorable chemical reactivity and stability. This study suggests that these identified compounds could be novel nature-derived AChE inhibitors, potentially contributing to AD treatment. However, further in-vitro and in-vivo studies are necessary to confirm their efficacy in biological systems. Future research will focus on developing these compounds into safe and effective drugs to combat Alzheimer's disease.

Design, Synthesis, Anti-Proliferative, and Apoptotic Assessment of Spirocyclopropyl Oxindole-Isatin Hybrids on Triple-Negative Breast Cancer.

A series of 1H-1,2,3-triazole-tethered spirocyclopropyl oxindole-isatin hybrids were synthesized using a copper-promoted click reaction and evaluated for their anti-proliferative activities against triple-negative breast cancer cell lines. The most potent compound in the series outperformed tamoxifen and 5-fluorouracil, with selectivity indices (SI) of 1.60 and 1.99 against MDA-MB-468 and MDA-MB-231 cancer cells, respectively. The Caspase 3/7 7-AAD assay showed live cell populations of 72.10% and 49.20% after 24 and 48 hours, respectively, indicating that the cytotoxic effect is mediated through the caspase apoptotic pathway. Molecular docking studies further suggested the compound's potential as an EGFR inhibitor, highlighting its promise as a therapeutic agent.

Synthesis Antimicrobial Activity and Chemotherapeutic Potential some Novel Benzimidazole Derivatives

Benzimidazole derivates play vital role in biological field such as antimicrobial, antiviral, antidiabetic, and anticancer activity. Therapeutic significance of these clinically useful drugs in treatment of microbial infections encouraged the development of some more potent and significant compounds. With the purpose of finding new chemical entities with enhanced antimicrobial activity, a series comprises 2-substituted-5-nitro benzimidazole derivatives were synthesized. Investigation of antimicrobial activity of the compounds was done by disc diffusion method using Gram-positive (S. aureus, S. mutans and B. subtilis), Gram-negative (E. coli, S. typhi and P. aeruginosa) bacteria. Some derivatives showed remarkable activity comparable to that of standard against Gram-positive and Gram-negative bacteria.

Pharmacokinetics and bioavailability of febrifugine in rat plasma determined by UPLC-MS/MS

AbstractFebrifugine, a potent quinazolinone compound derived from the Chinese herb Chang Shan (Dichroa febrifuga), exhibits diverse biological activities and has demonstrated anti-tumor effects by functioning as focal adhesion kinase (FAK) inhibitors. In this study, our objective was to establish a quantitative UPLC-MS/MS method and investigate the pharmacokinetic characteristics of febrifugine in rats following intravenous and oral administration routes. The rat tail vein was used for the collection of blood samples at designated time intervals following intravenous (2.0 mg kg−1) and oral (6.0 mg kg−1) administrations. Plasma samples were pretreated with acetonitrile as a protein precipitant and methylcytisine as an internal standard. Febrifugine concentration in rat plasma was determined using the UPLC-MS/MS method, and pharmacokinetic parameters were calculated using drug and statistics (DAS) software version for statistical analysis. The linear range of febrifugine in rat plasma was 1.5–1,500 ng mL−1, meeting the precision, recovery, and stability requirements for determination purposes. Febrifugine had a half-life (t1/2) of 3.2 ± 1.6 h after administered via intravenous route, while t1/2 was 2.6 ± 0.5 h after oral administration. The developed UPLC-MS/MS method is facile to operate while adhering to rigorous methodological verification standards, rendering it suitable for investigating the pharmacokinetics of febrifugine; and bioavailability was determined as 45.8%.

In vitro Antifungal Effects of Various Essential Oils against Aspergillus Crown Rot of Peanut

Synthetic fungicides that combat plant pathogenic fungi can enhance crop yields, ensuring stable crop production and market quality. However, the increase in the use of fungicides may cause to development of fungicide-resistant pathogen strains and the accumulation of fungicide residues in the food chain above safe limits. This situation underscores the need for improved fungal disease management through alternatives to synthetic fungicides. These alternatives include plant-derived compounds such as essential oils and extracts. Essential oils are known to be potent antifungal compounds against both human and plant pathogens. Aspergillus niger is a toxin-producing fungal disease agent that causes Aspergillus crown rot in peanuts. In this study, the antifungal activities of nine different essential oils from Foeniculum vulgare, Lippia citriodora, Origanum majorana, Origanum minutiflorum, Origanum onites, Origanum syriacum, Origanum vulgare, Salvia aramiensis and Thymus syriacus plants were evaluated against A. niger under in vitro conditions by using disc diffusion test. Among the nine essential oils tested, the highest antifungal activities were displayed by O. vulgare essential oil (with an inhibition zone diameter of 49.33 mm) which was followed by T. syriacus, O. onites, O. syriacum and O. minutiflorum essential oils (48.67, 47.00, 46.33 and 43.33 mm, respectively). The essential oils of F. vulgare, L. citriodora, and O. majorana showed relatively lower antifungal effects. The essential oil of S. aramiensis did not show antifungal effect against pathogen. The results indicated that plant essential oils could be valuable in promoting research aimed at developing new antifungal agent(s) for fungal disease management. However, further studies are needed to optimize the in vivo application conditions of essential oils against A. niger.

In-vitro and in-silico assessment of thiazole-thiazolidinone derivatives as selective inhibitors of urease and α-glucosidase.

Current research work aims to synthesize hybrid compounds with a thiazole-thiazolidinone structure, as potent inhibitors of urease and α-glucosidase enzymes. These compounds were characterize through1HNMR,13CNMR and HREI-MS techniques. These compounds were also evaluated for their potential to inhibit urease and α-glucosidase enzymes for the treatment of urinary tract infections (UTIs) and diabetes treatments. Moreover, molecular docking and ADMET analysis was carried out to confirm biological outcomes. Compounds-4 (IC50 = 1.80 ± 0.80 and 3.61 ± 0.59 μM against urease and α-glucosidase, respectively) exhibited significant effectiveness in inhibiting the activity of both enzymes in comparison to the conventional inhibitors thiourea and acarbose. Molecular docking experiments showed that potent compounds exhibited favorable binding orientations in the active sites of urease and α-glucosidase playing a pivotal role in inhibition profile of these compounds. These compounds were also investigated for their drug likeness and were found with desirable attributes for pharmaceutical development. Based on the findings of this research, these compounds have the potential to be developed into effective anti-diabetic and anti-urease treatments in the future.

Gallic Acid-Encapsulated PAMAM Dendrimers as an Antioxidant Delivery System for Controlled Release and Reduced Cytotoxicity against ARPE-19 Cells.

Poly(amidoamine) (PAMAM) dendrimers have gained significant attention in various research fields, particularly in medicinal compound delivery. Their versatility lies in their ability to conjugate with functional molecules on their surfaces and encapsulate small molecules, making them suitable for diverse applications. Gallic acid is a potent antioxidant compound that has garnered considerable interest in recent years. Our research aims to investigate if the gallic acid-encapsulated PAMAM dendrimer generations 4 (G4(OH)-Ga) and 5 (G5(OH)-Ga) could enhance radical scavenging, which could potentially slow down the progression of age-related macular degeneration (AMD). Encapsulation of gallic acid in PAMAM dendrimers is a feasible alternative to prevent its degradation and toxicity. In vitro investigation of antioxidant activity was carried out using the DPPH and ABTS radical scavenging assays, as well as the FRAP assay. The IC50 values for DPPH and ABTS assays were determined through nonlinear dose-response curves, correlating the inhibition percentage with the concentration (μg/mL) of the sample and the concentration (μM) of gallic acid within each sample. G4(OH)-Ga and G5(OH)-Ga possess significant antioxidant activities as determined by the DPPH, ABTS, and FRAP assays. Moreover, gallic acid-encapsulated PAMAM dendrimers inhibit H2O2-induced reactive oxygen species (ROS) production in the human retinal pigment epithelium ARPE-19 cells, thereby improving antioxidant characteristics and potentially retarding AMD progression caused by ROS. In an evaluation of cell viability of ARPE-19 cells using the MTT assay, G4(OH)-Ga was found to reduce cytotoxic effects on ARPE-19 cells.

Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR.

The treatment of patients with nonsmall cell lung cancer (NSCLC) using epidermal growth factor receptor (EGFR) inhibitors is complicated by drug-sensitive activating L858R/T790M and L858R/T790M/C797S mutations. To overcome drug resistance, a series of furopyridine (PD) compounds were virtually screened to identify potent EGFR inhibitors using molecular docking and molecular dynamics (MD) simulations based on the solvated interaction energy (SIE) method. Several PD compounds identified from virtual screening demonstrated the potential to suppress both wild-type and mutant forms of EGFR, with IC50 values in the nanomolar range. Among these, PD18 and PD56 exhibited highly potent inhibitory activity against both wild-type and mutant forms of EGFR, surpassing the efficacy of known drugs. Additionally, both PD compounds were cytotoxic to NSCLC cell lines (A549 and H1975) while being nontoxic to normal cell lines (Vero). The interaction mechanisms of both PD compounds complexed with wild-type and mutant forms of EGFR were elucidated through 500 ns molecular dynamics simulations. The predicted binding affinity from molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) correlated well with the experimental binding affinity derived from IC50 values. Furthermore, it was observed that van der Waals interactions, rather than electrostatic interactions, played a significant role in interacting with EGFR's active site. The strong inhibitory activity against EGFR was attributed to two key residues, M793 and S797, via hydrogen bonding, corresponding with lower solvent accessibility and a higher number of atomic contacts. Therefore, these potent compounds could be developed as promising drugs targeting both wild-type and mutant EGFR for the treatment of NSCLC.

Perspectives on Applications of 19F-NMR in Fragment-Based Drug Discovery.

Fragment-based drug discovery is a powerful approach in drug discovery, applicable to a wide range of targets. This method enables the discovery of potent compounds that can modulate target functions, starting from fragment compounds that bind weakly to the targets. While biochemical, biophysical, and cell-based assays are commonly used to identify fragments, 19F-NMR spectroscopy has emerged as a powerful tool for exploring interactions between biomolecules and ligands. Because fluorine atoms are not naturally present in biological systems, 19F-NMR serves as a sensitive method for fragment screening against diverse targets. Herein, we reviewed the applications of 19F-NMR in fragment screening, highlighting its effectiveness in identifying fragments that bind weakly to various targets such as proteins and RNA. The accumulated evidence suggests that 19F-NMR will continue to be a crucial tool in drug discovery.

Osthole induces accumulation of impaired autophagosome against pancreatic cancer cells

Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide, and few effective therapeutics are available. Osthole (OST), a natural coumarin, has been proven to be a potential anticancer compound. In this study, we found that OST significantly inhibited PC growth both in vitro and in vivo. Notably, the anti-PC effect of OST is mediated by excessive autophagosome accumulation and consequent apoptosis in PC cells. Mechanistically, OST increased the number of autophagosomes via two pathways. First, OST induced autophagy initiation by suppressing the Akt/mTOR signaling pathway. Second, OST induced autophagic arrest by blocking autophagosome-lysosome fusion. Consistently, inhibition of autophagy initiation restored PC cell growth, whereas autophagic flux inhibitors exacerbated the antitumor effect of OST in PC cells, suggesting a cytotoxic role of OST-induced autophagosome accumulation. In addition, we found that OST upregulates the expression of activating transcription factor 3 (ATF3), resulting in inactivation of the Akt/mTOR signaling pathway and autophagy initiation in PC cells. ATF3 overexpression increased the activation of autophagy, and inhibition of ATF3 expression decreased autophagy. Taken together, our study provides new insights into the OST-induced growth inhibitory effect on PC cells, suggesting a promising potential therapeutic role of OST for PC treatment.

4′-Demethylpodophyllotoxin functions as a mechanism-driven therapy by targeting the PI3K-AKT pathway in Colorectal cancer

The treatment of colorectal cancer (CRC) poses significant challenges in terms of drug resistance and poor prognosis, necessitating the exploration of effective therapeutic strategies. In this study, high-throughput drug screening was utilized to identify Chinese herbal medicines with notable therapeutic effects on CRC. Among the compounds identified, 4′-demethylpodophyllotoxin (DOP), a derivative of podophyllotoxin, emerged as a potent anti-cancer compound. DOP exhibited time- and dose-dependent growth inhibition on CRC cell lines and tumor organoids derived from patients. RNA-seq revealed that DOP activated the PI3K-AKT pathway, leading to tumor cell apoptosis and cell cycle arrest at the G2/M phase. Additionally, DOP induced DNA damage in CRC cells. To further validate its therapeutic efficacy in CRC, the DLD1-derived xenograft model demonstrated that DOP effectively suppressed CRC growth in vivo. In conclusion, these findings highlight the significant therapeutic potential of DOP as an anti-tumor drug for treating CRC, thereby opening new avenues for investigating Podophyllotoxin derivatives in this specific field.

High-Throughput Drug Screening in Chondrosarcoma Cells Identifies Effective Antineoplastic Agents Independent of IDH Mutation

The term chondrosarcoma refers to a rare and heterogeneous group of malignant cartilaginous tumors that are typically resistant to chemotherapy and radiotherapy. Metastatic chondrosarcoma has a poor prognosis, and effective systemic therapies are lacking. Isocitrate dehydrogenase (IDH) mutations represent a potential therapeutic target, but IDH inhibitors alone have shown limited clinical efficacy to date. Although the role of conventional chemotherapy is still subject to debate, some evidence suggests it may provide therapeutic benefits in advanced cases. In this study, we aimed to identify effective compounds for combination therapy in chondrosarcoma. Using high-throughput screening, we evaluated a panel of anticancer agents in IDH1-mutant chondrosarcoma cell lines and their mutant IDH1 knockout derivatives. The top 20 most potent compounds were identified across all cell lines, irrespective of IDH mutation status. Representative drugs selected for further investigation included docetaxel, methotrexate, panobinostat, idarubicin, camptothecin, and pevonedistat. These drugs inhibited colony formation, induced apoptosis and cell cycle arrest, and exhibited synergistic antitumor activity in two-drug combinations. In conclusion, we identified several highly effective agents with potent anti-tumor activity in chondrosarcoma cells, independent of IDH mutation status. These agents represent promising candidates for chondrosarcoma therapy and warrant further preclinical investigation and potential inclusion in clinical trials.

Characterization of naphthoquinones as inhibitors of glutathione reductase and inducers of intracellular oxidative stress

ABSTRACT Glutathione reductase (GR), one of the most important antioxidant enzymes in maintaining intracellular redox homeostasis, has become a novel target to suppress cancer cell growth and metastasis. In this work, we evaluated a series of naphthoquinones (NQs) as potential GR inhibitors and elucidated the mechanism of inhibition. NQ-6, one of the most potent compounds among this series, inhibited GR in vitro and in vivo and was identified as a competitive and irreversible inhibitor. The Ki and kinact values of NQ-6 were determined to be 17.30 ± 3.63 μM and 0.0136 ± 0.0005 min-1, respectively. The tandem mass spectrometric analysis revealed that the two substrate binding sites Cys61 and Cys66 of yeast GR were modified simultaneously through arylation or only Cys66 was covalently modified by NQ-6. Intracellular reactive oxygen species, collapsing of mitochondrial membrane potential and protein S-glutathionylation elevation were induced by NQ-6. NQs can be valuable compounds in GR inhibition and oxidative stress-related research.

Highly Efficient and One-pot New Betti Bases: PEG-400 and Al2O3 Mediated Synthesis, Optimizations, and Cytotoxic Studies

Background: Multicomponent reactions (MCRs) have proven as one of the best alternatives to minimize several environmental consequences, mainly the use of hazardous chemicals, byproducts, and severe production processes. Literature reveals that MCRs with PEG-400 and metal oxide-based greener media provide a new and useful strategy for the construction of biologically potent organic systems. Objective: The present study aimed to synthesize newer Betti bases by a modified Betti reaction employing a highly efficient catalyst for the direct synthesis of a novel class of non-racemic amino benzyl naphthol ligands under green solvent media. The involvement of the articulated framework (4a-4j) was studied against nine cancer panels (NCI-60 cell lines) in terms of inhibiting/killing cancer cells. Methods: For the modification of the Betti reaction, we used 2-aminopyridin-3-ol, aromatic aldehydes, and a naphthol system using greener media employing PEG-400 and alumina as a prime active and highly selective catalyst. Furthermore, the antiproliferative activity against NCI-60 human cancer cell lines (GI50) was used for the development of pharmacologically active compounds and exhibited the single dose (10-5 M) study. Results: Based on greener media synthesis, recompenses of ease of workup, less reaction time, higher yield, and higher atom economy, as well as environmentally friendly, were reported. Betti bases were obtained at a yield of 87-98% and characterized by spectroscopic techniques. Among the synthesized scaffolds, compound 4b was found to be extra potent in melanoma cancer [MDAMB- 435], while compound 4h showed promising inhibition in leukemic cancer cell lines [HL- 60(TB) and MOLT-4]. Conclusion: A straightforward way for an efficient synthesis of Betti bases was developed via the reaction of naphthol and aldehydes with amines in PEG-400 media. An Al2O3 was effectively catalyzed in the Betti reaction in excellent yields without the formation of any other by-product in atom economy and environmentally benign way. The newly synthesized hybrids were tested in vitro against a panel of cancer cell lines, and some of the compounds exhibited significant inhibitory anti-proliferative effects. The most potent compounds (4b and 4h) showed interesting results, and compound 4b was found extra potent in melanoma cancer cell lines with -62% GI values.

Design, synthesis, biological evaluation and molecular docking study of novel quinolone derivatives as potent HDAC1 (Histone Deacetylase) inhibitors and anticancer agents

Histone deacetylases (HDACs), especially HDAC1, are attractive targets for anticancer drug design because of their significant role in transcriptional repression and chromatin remodeling. Benzamide groups are widely reported as the most effective zinc binding groups (ZBGs) in design of HDAC inhibitors. Quinolone derivatives, exhibiting various therapeutic effects, are attractive scaffolds for developing novel HDAC inhibitors with potentially supposed therapeutic profiles. To explore the potential of 4-quinolones as a novel scaffold for a cap of HDACis, 14 novel structures were rationally designed and synthesized. Four cancer cell lines (HCT116, HT29, MCF7, and A549) and one normal cell (CHO) were applied to investigate the cytotoxicity of synthesized compounds. Furthermore, the inhibitory activity of the synthesized compounds was analyzed against pan-HDAC isozymes (HDAC1, HDAC2, HDAC3 and HDAC6). Five compounds (5a, 5b, 5c, 5e and 5h) showed strong cytotoxicity and HDAC inhibition even superior to entinostat as the reference drug. Collectively, these results suggest that compounds with an electron-donating group at the positions 6 or 8 of the quinolone ring (cap) appear to enhance the anti-proliferative potency. After performing induce-fit docking (on HDAC1, 2, 3, 6) for all the synthesized compounds, a significant correlation was identified between the MTT results, the inhibitory activity of pan-HDAC, and the docking scores of HDAC1. Therefore, compounds 5e and 5a (the most potent compounds) were identified as the most favorable leads for further investigation of HDAC1-specific enzyme inhibition. Compounds 5a and 5e showed impressive HDAC1 inhibitory potency with IC50 values of 0.48 μM and 0.36 μM, respectively, equal or more than that of Entinostat. Compound 5e (3 µM) also exhibited significant induction of apoptosis in the HCT116 cell line (the percentage of apoptotic cells was 81.87%), even stronger than the reference drug Entinostat (the percentage of apoptotic cells was 37.5%) at the same concentration which is consistent with their antiproliferative activities as well. 100 ns molecular dynamic (MD) simulation revealed that compound 5e can form stable interactions with HDAC1 through coordination with zinc ion, strong hydrophobic interactions and formation of hydrogen bonds. These results suggested that compound 5e can be promising lead for further development of potent anticancer and HDAC inhibitor drugs.

Development of new LSM-83177 analogues as anti-tumor agents against colorectal cancer targeting p53-MDM2 interaction

LSM-83177, a phenoxy acetic acid derivative, is a small molecule reported for its promising anti-tumor properties. Via inhibiting the interaction between MDM2 and p53, LSM-83177 can elevate the active p53 levels within cells, thereby promoting apoptosis and inhibiting tumor growth. Also, LSM-83177 has been shown to inhibit GST activity in colorectal cancer HT29 cells. In the current work, novel LSM-83177 hydrazone analogs 5a-f, 7a-b, 10a-e, and 13a-b have been designed according to the structure features of LSM-83177 and their binding mode in the active site of MDM2. The anti-cancer activity of the newly synthesized analogs is evaluated against the HT29 cell line. The most potent compounds, 7a and 10a, showed IC50 = 12.48 and 10.44 µg/ml, respectively, when compared with Cisplatin (IC50 = 11.32 µg/ml) as a reference drug. Compounds 7a and 10a were introduced for further inspection for p53-MDM2 protein–protein interaction, where they displayed IC50 values of 3.65 and 11.08 µg/ml, respectively. Furthermore, hydrazones 7a and 10a increased the p-53 expression levels by 3.22– and 4.25-fold, respectively; in addition, they effectively reduced the GST expression levels in HT29 cancer cells with 0.56- and 0.30-fold increments in comparison to the untreated control.

Synthesis of Polyoxygenated 4,5-Diarylpyridazines with Antiproliferative and Antitubulin Activity via Inverse Electron-Demand Diels-Alder Reaction of 1,2,4,5- Tetrazine

: The synthesis of a series of multifunctionalized 4,5-diarylpyridazines via inverse electron-demand Diels-Alder reaction between highly oxygenated diarylacetylenes and unsubstituted 1,2,4,5-tetrazine was developed using polyalkoxybenzenes isolated from industrial essential oils as starting material. The reaction proceeded smoothly to afford combretastatin A-4 analogs with pyridazine linker in consistently high yield. In a phenotypic sea urchin embryo assay, diarylpyridazine with 3,4,5-trimethoxyphenyl and 3-amino-4- methoxyphenyl aryl rings was identified as a potent antimitotic microtubule-destabilizing compound.

Design, Synthesis and Fungicidal Activity of N-(5-Phenyl-1,3,4-Thiadiazol-2-yl)-N-((1-Phenyl-1H-1,2,3-Triazol-4-yl) Methyl) Benzamide Derivatives

Objective: Plant pathogens are serious hazards to agricultural production, but existing drugs have problems such as increased resistance of pathogenic bacteria and environmental pollution, and there is a need to find high-efficiency, low-toxicity fungicides with novel chemical structures. Methods: 5-phenyl-1,3,4-thiadiazol-2-amine was used as the starting material, and 20 new thiadiazole-linked compounds were designed and synthesized. Their in vitro inhibitory activities against plant pathogenic fungi were tested using a mycelium growth inhibition assay, and the relationship between the antifungal activity of the target compounds and their molecular structures was preliminarily discussed. Results: Bioassay results revealed that most of the title compounds exhibited excellent in vitro fungicidal activity, in which compound D16 showed the highest activity against Rhizoctonia solani (EC50 = 0.0028 μmol·L−1), D12 against Botrytis cinerea (EC50 = 0.0024 μmol·L−1), and D5 against Stemphylium lycopersici and Curvularia lunata (EC50 = 0.0105 μmol·L−1, 0.005 μmol·L−1). The structure activity relationship (SAR) was also discussed and the results are of great significance for the structural optimization and development of more effective thiadiazole antibacterial compounds. Conclusion: The results of this study are important for structural optimization and development of more potent thiadiazole antimicrobial compounds.