Compound 5a Research Articles

Synthesis, Biological Activities, and Molecular Docking Studies of 15-Site Matrine Based Isatohydrazone Derivatives as Potential Anticancer Agents.

To acquire matrine derivatives with enhanced anticancer activity, we designed and synthesized twenty-one 15-site matrine based isatohydrazone derivatives were designed and synthesized. The anti-proliferative activity of all the compounds against human cervical cancer cells (HeLa), human colon cancer cells (HCT116), and non-small cell lung cancer cells (A549) was examined by the MTT method. The majority of the compounds exhibited superior anticancer activity compared to matrine. Among them, compound 5a displayed the most potent anti-proliferative activity, with IC50 values of 9.02±0.33 μM (HeLa), 10.49±1.09 μM (HCT116), and 15.23±0.12 μM (A549), respectively. Compound 5a can also induce cell cycle arrest in the G0/G1 phase and trigger apoptosis, as well as inhibit cell clonal formation and migration. Molecular docking experiments have demonstrated that compound 5a can form hydrogen bonds and hydrophobic interactions with EGFR-related protein 7AEI.

Discovery of New Immunomodulatory Anticancer Thalidomide Analogs: Design, Synthesis, Biological Evaluation and In Silico Studies.

New thalidomide analogs have been designed and synthesized by hybridizing the immunomodulatory gutarimide moiety with three antiproliferative nuclei: quinazolinedione, phthalazinedione, and quinoxalinone. The biological results revealed the strong impact of quinazoline derivatives 7a and 28, and phthalazine based 20a against HepG-2, MCF-7, PC3, and HCT-116 cell lines, compared to thalidomide. In particular, compound 20a was the most promising as it had far better biological activity than thalidomide with regard to inhibition of TNF-α, IL-6, caspase 3, COX-I/II, and VEGFR-2, as well as cell cycle arrest, and apoptosis rate enhancement in MCF-7 cells, the most sensitive cell line to the current new molecules. Compound 20a caused reduction in levels of TNF-α and IL-6 by 75.22% and 82.51%, respectively. It elevated the caspase-3 level by 7.21-fold. Furthermore, IC50 against COX-I, COX-II, and VEGFR-2 were 0.65 μM, 0.33 μM, and 232 nM, respectively. In addition, it raised the apoptosis rate from 65.65% to 99.89%. Moreover, 20a was further examined through a docking study and a 200 ns molecular dynamics simulation for its complex with VEGFR-2, along with computational ADME properties. This work suggests the high significance of compounds 20a, 7a and 28, as lead compounds for development of new effective immunomodulatory antitumor drugs.

Discovery of 4-(4-(3-(1-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole-2-yl)isoxazol-5-yl)phenyl)morpholine as a novel c-Myc inhibitor against lung cancer in vitro and in vivo

The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of D347–2761, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound A1 displayed IC50 values of 6.32 μM and 11.39 μM against the A549 and NCI–H1299 lung cancer cell lines, respectively, while compound A5 exhibited IC50 values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds A1 and A5 exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound A5 demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound A5 exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound A5 holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy.

Synthesis and biological evaluation of novel isobenzofuran-1(3H)-one derivatives as antidepressant agents

A series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as antidepressants. Firstly, the serotonin reuptake inhibition of these compounds was tested in vitro, and most of them exhibited activity. Particularly, compounds 9d, 10a, and 10c demonstrated superior inhibitory effects and possibly avoided addiction via the μ-opioid receptor and CCK-B receptor. Secondly, the antidepressant effect of compound 10a was evaluated using chronic restraint stress (CRS)-induced mice. The results showed that compound 10a significantly improved CRS-induced depression-like behavior by increasing the neurotransmitters 5-HT in the cortex and THP2 expression in the hippocampus. Thirdly, compound 10a was further investigated and found to enhance CRS-induced hippocampal neuron damage recovery and elevate the expression of synaptic-associated proteins such as BDNF, TrkB, PSD95, and Spinophilin in CRS-induced mice. These findings suggested that novel isobenzofuran-1(3H)-one derivative showed efficacy in treating depression, with compound 10a emerging as a potential lead compound warranting further investigation.

Synthesis of Paracetamol‐Appended Bis 1,2,3‐Triazole Analogues as Anti‐Inflammatory Agents

AbstractParacetamol‐based bis 1,2,3‐triazole analogues were synthesized involving copper‐catalyzed click chemistry protocol. The new compounds were characterized by 1H NMR, 13C NMR, and mass spectral techniques. All the compounds were evaluated for their in vitro anti‐inflammatory properties using diclofenac as standard reference. The compound 6b with chlorine and fluorine functions displayed outstanding activity with IC50 values of 7.34 ± 0.45 µM and 7.84 ± 0.47 µM, respectively. Compound 6g with methyl and fluorine functions displayed best activity with IC50 values of 9.34 ± 0.22 µM and 9.40 ± 0.35 µM, respectively. Compound 6i, 6k, 6f, 6a, 6e, 6h, 6j, and 6l exhibited promising activity with respect to diclofenac. Using PyRx tool, the molecular docking study against crystal structure of COX‐2 proved the binding efficacies with notable binding interactions.

Metal-Free Synthesis, Single Crystal Analysis and Photophysical Behavior of p-Terphenyls

A simple and convenient metal-free approach for synthesizing p-terphenyls 7a–f is presented through a carbanion-induced ring transformation reaction involving 6-biphenyl-2H-pyran-2-ones 5 with pyruvic acetyl dimethyl aldehyde 6. Further the prepared dimethoxy p-terphenyls 7b-c,f were converted into diethoxy p-terphenyls 8a-c. The base-mediated ring transformation reactions proceeded smoothly under mild reaction conditions, resulting the formation of ring transformation products 7a-f and 8a-c in good to excellent yields. This synthetic approach allows the incorporation of both electron-withdrawing and electron-donating functionalities into p-terphenyl framework. Moreover, the structure of compound 7a was confirmed by its single crystal X-ray analysis. Additionally, the photophysical properties of synthesized p-terphenyls were analysed using UV-visible and fluorescence spectroscopy. Interestingly, the synthesized p-terphenyls 7a–f showed blue fluorescence in chloroform. The solvatochromic behaviour and concentration studies of compound 7d was also perforemd. Additionally, the thermal stability characteristics of compound 7d was also studied using TG and DTA analysis.

Non-nucleophilic base promoted synthesis of azo-linked oxazolone-pyrazole hybrids: Antimicrobial, antitubercular, anticancer evaluations and in-silico modeling insights

Ten new non-nucleophilic base (DBU) catalyzed oxazolone-bearing pyrazole derivatives were created to treat infectious diseases caused by bacterial, mycobacterial strains, and cancerous cell lines. Compounds 7b and 7c showed excellent antibacterial and antifungal activity. Compound 7b was highly effective against M. tuberculosis H37Rv, with a MIC of 0.06 μg/mL and significant binding affinities to AcrB of E. coli (−12 Kcal/mol), TriABC of P. aeruginosa (−12.5 Kcal/mol), and MepR of S. aureus (−10.6 Kcal/mol). Based on the findings, compounds 7b, 7c, and 7e exhibit proficient binding affinity with two essential targets, namely Enoyl-[acyl-carrier-protein] reductase and Topoisomerase I, of M. tuberculosis. Compound 7b showed superior cytotoxic activity against all cancer types except leukemia with GI50 values of 1.26–1.83 µM and LC50 values of 5.36–7.88 µM. Compound 7a demonstrated remarkable anticancer activity against colon, melanoma, ovarian, renal, and breast cancer cell lines with GI50 values of 1.60–2.55 µM.

Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A

The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO4) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC50] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO4, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC50 = 1.0 μg/mL) and A. pacificum (EC50 = 0.47 μg/mL), being 3–5-fold more potent than natural bacillamide A, Diuron, and CuSO4. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO4 and provides a promising candidate for the development of new algicides, worthy of further investigation.

Potential Antioxidant Compounds from the Spores of Dicranopteris linearis and the Branches of Averrhoa bilimbi

This study focused on bio-guided isolation based on antioxidant activities from Dicranopteris linearis spores and Averrhoa bilimbi branches. The total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activities of the extracts were determined. For D. linearis spores, the ethyl acetate (EA) extract exhibited the highest TPC (120.13 ± 0.04 mg GAE/g) and TFC (21.94 ± 0.30 mg QE/g), along with strong DPPH antioxidant activity (96.3 ± 0.3% inhibition, IC50 of 39.4 ± 0.3 µg/mL). For A. bilimbi branches, the n-hexane–ethyl acetate (HEA) extract showed the highest TPC (165.21 ± 0.24 mg GAE/g) and TFC (26.20 ± 0.01 mg QE/g), with significant DPPH antioxidant activity (89.6 ± 0.7% inhibition, IC50 of 39.7 ± 1.9 µg/mL). Phytochemical investigation led to the identification of ten compounds (D1–D10) from D. linearis spores and twelve compounds (A1–A12) from A. bilimbi branches. Notably, compound A1 was identified as a new natural compound. The chemical structures were elucidated through NMR spectroscopy and comparison with existing literature. The antioxidant activities of selected compounds (D3–D5, D8–D10, and A1–A11) were evaluated using DPPH and ABTS free radical scavenging assays. Among them, compound A3 exhibited the strongest antioxidant activities (IC50 of 7.1 ± 0.1 µg/mL for DPPH and 14.8 ± 0.1 for ABTS, respectively). The results of this study highlight the potential of D. linearis and A. bilimbi for use in natural product-based antioxidant applications.

Structural Modification and Pharmacological Evaluation of (Thiadiazol-2-yl)pyrazines as Novel Piezo1 Agonists for the Intervention of Disuse Osteoporosis.

Piezo1 plays a pivotal role in regulating bone remodeling and homeostasis and has emerged as a promising target for chemical intervention in disuse osteoporosis. Nevertheless, the development of small-molecule Piezo1 agonists is still in its infancy, and highly efficacious Piezo1 agonists are urgently required. In this study, by shedding light on the structural novelty of the canonical Piezo1 agonist Yoda1, we initiated a structural optimization campaign based on the (thiadiazol-2-yl)pyrazine scaffold. A deuterated compound 12a was identified to be the most potent candidate against Piezo1 with an EC50 value of 2.21 μM, which was over 20-fold more potent than the reference Yoda1. This compound effectively activated Piezo1 and initiated Ca2+ influx in MSCs and promoted MSC osteogenesis via activating the Ca2+-related Erk signaling pathway. Furthermore, compound 12a was found to alleviate disuse osteoporosis with a desirable safety profile in a HU (hindlimb-unloading) rat model, thus warranting it as a potential probe for further investigation.

A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg-1·d-1) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg-1·d-1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

Design of some phthalazine molecules as novel VEGFR-2 target inhibitors through 3D-QSAR modeling, molecular docking and dynamic simulation and pharmacokinetics profiling

AbstractBreast cancer is one of the dominant cause of cancer-related mortality in females, with an incidence of approximately 1.3 million cases annually, necessitating the development of effective therapeutic strategies. In this study, 3D-QSAR models were reported based on Phthalazine derivatives as VEGFR-2 inhibitors. The activities of these derivatives were correlated with the steric (S), electrostatic (E), hydrogen bond acceptor (A), and donor (D), and hydrophobic (H) fields, which served as critical parameters in model development. Statistical studies of these models showed that the best models are; CoMFA_S (Q2 = 0.623, R2 = 0.941), and CoMSIA_E + D (Q2 = 0.615, R2 = 0.977). Based on the insights from the model fields and docking simulation of the template (compound 17), twelve molecules were designed. These novel molecules exhibited stronger potency compared to the template and the standard, Sorafenib. Compound 17A emerged as the most potent, with pIC50 = 5.98, for CoMFA_S and 5.85, for CoMSIA_E + D, and a strong docking affinity of − 97.271 kcal/mol, therefore subjected to a 100-ns MD simulation. Results indicate better interaction and stabilizing potential over Sorafenib, due to the lower RMSD, RMSF, Rg, values and favorable hydrogen bond analyses. These conclusions were validated by Gibbs free energy analysis and MM-GBSA calculations, revealing a more favorable interaction free energy of − 18.48 kcal/mol related to Sorafenib. Furthermore, these designed compounds demonstrated promising pharmacokinetic profiles.

Synergism of Computational Simulation Technique and Machine Learning Algorithm for Prediction of Anticorrosion Properties of Some Antipyrine Derivatives.

This study aimed to predict the selected antipyrine compounds' inhibitory efficiencies and anticorrosion properties in a hydrochloric acid (HCl) environment. Molecular descriptors and input variables were obtained using density functional theory (DFT), and the variance inflation factor (VIF) was employed to reduce redundant variables, leading to the selection of seven quantum chemical descriptors as input variables. Using machine learning techniques such as K-nearest neighbor (KNN) and artificial neural network (ANN), a predictive model was built for 39 antipyrine compounds with known corrosion inhibition efficiencies for carbon and low alloy steel in hydrochloric acid solutions. The models' predictive capability was assessed using cross-validation, with the ANN model showing superior performance, achieving a coefficient of determination (R2) value of 0.715 compared to 0.548 for the KNN model. Performance metrics such as the mean square error (MSE), mean absolute error (MAE), and root-mean-square error (RMSE) further confirmed the superiority of the ANN model over the KNN model. The corrosion inhibition efficiencies (CIEs) of the selected antipyrine compounds ranged from 68.78 to 99.79%, with compound A1 demonstrating the highest CIE of 99.79% and compound A3 the lowest, as evaluated by the ANN model. Analysis of Fukui index parameters obtained from the Mulliken population analysis suggested that the nucleophilic and electrophilic sites play a crucial role in the interactions between the inhibitor and the metal atom through electron donor-acceptor interactions. Moreover, the energy of adsorption (Eads) in kcal·mol-1 decreased in the order of A1 (-187.8) > A2 (-132.0) > A2 (-84.4), with the high negative value of Eads indicating strong and spontaneous adsorption. Further analysis using radial distribution functions and molecular dynamics simulations revealed that inhibitor A1 exhibited predominantly chemisorption, inhibitor A2 showed a mixed type, and inhibitor A3 demonstrated predominantly physisorption, aligning well with the results of the predictive studies.

Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis

AbstractFerroptosis is a novel form of cell death driven by oxidative damage, and is implicated in various pathological conditions, including neurodegenerative diseases, retinal damage, and ischemia‐reperfusion injury of organs. Inhibiting ferroptosis has shown great promise as a therapeutic strategy for these diseases, underscoring the urgent need to develop effective ferroptosis inhibitors. Although Ferrostatin‐1 (Fer‐1) is a potent ferroptosis inhibitor, its susceptibility to oxidation and metabolic inactivation limits its clinical utility. In this study, the accumulation of peroxides and the resulting oxidative damage in the cellular microenvironment during ferroptosis were utilized to design Ferrostatin‐1 prodrugs with reactive oxygen species‐responsive features. This approach led to the development of a series of ferroptosis inhibitors that were capable of recognizing oxidative damage in diseased areas, allowing for targeted release and improved stability. The novel compounds demonstrated significant inhibitory effects and selectivity against RSL‐3‐induced ferroptosis in HK‐2 cells, with compound a1 exhibiting an EC50 of 15.4 ± 0.7 μM, outperforming Fer‐1. These compounds effectively identify the oxidative microenvironment associated with ferroptosis, enabling the targeted release of Fer‐1, which prevents lipid peroxide accumulation and inhibits ferroptosis. This strategy holds promise for treating diseases related to ferroptosis, offering a targeted and intelligent therapeutic approach.

New acetophenone scaffolds: Synthesis, antifungal activities, biocompatibility, molecular docking, ADMET analysis and dynamic simulations

In this work, the chemical reactivity of 2-cyano-N′-(1-phenylethylidene)acetohydrazide (3) towards different aldehydes is utilized to synthesize binary and fused heterocyclic compounds, including arylidenes 6, 7, 12, 13, 14, 18a-c, 19a,b, 20, chromone 23, and chromene derivatives 24, 26a-c, 29, and 30. The capability of newly synthesized compounds to inhibit fungal growth of Aspergillus niger ATCC 16404, A. flavus ATCC 9643, Penicillium chrysogenum ATCC 10106, and Rhizopus oryazae ATCC 96382 are assessed. It is observed that compound 29 had strong antifungal activity against all fungi with MFIC values varying from 250 to 1000 µg/ml, while compound 18a demonstrated potent antifungal effect against A. niger and A. flavus. In addition, it is found that compound 29 was cytotoxic to Vero cells at doses of 1000–500 µg/ml; however, no discernible variation was observed between the concentrations of 250–31.25 µg/ml. Moreover, the interactions between the promising compounds 18a, 19b, and 29 and antifungal target proteins are assessed using molecular docking. The results of the docking simulations demonstrated that these compounds demonstrated optimal binding energies and effectively engaged with the active sites of FDC1 protein in A. niger, UDP-N-acetylglucosamine in A. fumigatus, Adenosine 5′-phosphosulfate kinase in P. chrysogenum, and protease in Rhizopus oryazae. These interactions involved various types of molecular interactions, indicating that these compounds have the ability to impede enzymes and exhibit strong antimicrobial effects. Furthermore, the in-silico ADMET profiles of compounds 18a, 19b, and 29 reveal that they adhere to the Lipinski rules, suggesting favorable physicochemical properties. Also, MD simulations revealed stable complexes of 29 with anti-fungal receptors including fdc1, UDP-N-acetylglucosamine, APS kinase, and protease with RMSD (0.1–0.8, 0.19–0.25, 0.20–0.30, and 0.20–0.35 nm), RMSF (0.1–0.8 nm), SASA (140–155, 130–140, 135–145, and 120–130 nm2), and Rg (1.90–2.00, 1.80–1.90, 2.40–2.50, and 2.10–2.20 nm) respectively. Our results provide potential and promising compounds for fungal infection diseases.

In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi

Chagas disease is a prevalent health problem in Latin America which has received insufficient attention worldwide. Current treatments for this disease, benznidazole and nifurtimox, have limited efficacy and may cause side effects. A recent study proposed investigating a wide range of nitroindazole and indazolone derivatives as feasible treatments. Therefore, it is proposed that adding a nitro group at the 5-position of the indazole and indazolone structure could enhance trypanocidal activity by inducing oxidative stress through activation of the nitro group by NTRs (nitroreductases). The study results indicate that the nitro group advances free radical production, as confirmed by several analyses. Compound 5a (5-nitro-2-picolyl-indazolin-3-one) shows the most favorable trypanocidal activity (1.1 ± 0.3 µM in epimastigotes and 5.4 ± 1.0 µM in trypomastigotes), with a selectivity index superior to nifurtimox. Analysis of the mechanism of action indicated that the nitro group at the 5-position of the indazole ring induces the generation of reactive oxygen species (ROS), which causes apoptosis in the parasites. Computational docking studies reveal how the compounds interact with critical residues of the NTR and FMNH2 (flavin mononucleotide reduced) in the binding site, which is also present in active ligands. The lipophilicity of the studied series was shown to influence their activity, and the nitro group was found to play a crucial role in generating free radicals. Further investigations are needed of derivatives with comparable lipophilic characteristics and the location of the nitro group in different positions of the base structure.

Thiazepine-based Hybrids as Promising Anti-colon Cancer Agents: Design, Synthesis, Computational and In Vitro Screening.

Novel thiazepine-based hybrids (9a-d) were designed and synthesized to create lead molecules with exceptional anti-colon cancer efficacy. Analytical methods, including IR, NMR, and HR-MS, characterized the synthesized compounds. The in vitro colorectal study was carried out to compare the biological activity of newly developed compounds with the computational data. The tested compounds induced cytotoxicity in HT-29 cells for both 24h and 48h in a dose-dependent manner. However, compound 9a induced cytotoxicity at much higher concentrations compared to the rest of the compounds. 9b and 9c caused 50% cell death (compared to the untreated cells) at a dose of ~ 50µM and 40 µM in case of 24-hour exposure, respectively. On the contrary, for 48h exposure, both 9b and 9c induced 50% cell death concerning untreated cells at a dose of around ~20 µM, whereas 9d exhibited 50% cell death at 5 µM in the case of 48 h exposure. In silico ADMET was also carried out to understand the pharmacokinetics and safety profiles of the drug candidates. We found some of the critical targets of these compounds, which eventually will be integral to exploring the mechanistic actions of these compounds in colon cancer.

Synthesis and biological evaluation of 1, 2, 3-triazole incorporated pyrrole derivatives as anticancer agents

A new series of 1,2,3-triazole skeleton incorporated pyrrole derivatives (11a–j) were developed and their chemical structures were confirmed by analytical data. Further, the anticancer profile of these newly derived compounds 11a–j was assessed against four types of human cancer cell lines such as human breast cancer (MCF-7), lung cancer (A549), colon cancer (Colo-205) and ovarian cancer (A2780) by employing of the MTT method and was compared with etoposide used as a positive control. Most of the examined derivatives displayed moderate to good activity compared with the positive control. Among them, five compounds 11a, 11b, 11c, 11d, and 11e showed more potent activity. Particularly, compound 11a showed superior activity.

Discovery of Novel Thiazole-Based SIRT2 Inhibitors as Anticancer Agents: Molecular Modeling, Chemical Synthesis and Biological Assays.

The search and development of effective sirtuin small molecule inhibitors (SIRTIs) continues to draw great attention due to their wide range of pharmacological applications. Based on SIRTs' involvement in different biological pathways, their ligands were investigated for many diseases, such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases and autoimmune diseases. The elucidation of a substantial number of SIRT2-ligand complexes is steering the identification of novel and more selective modulators. Among them, SIRT2 in the presence of the SirReal2 analog series was the most studied. On this basis, we recently reported structure-based analyses leading to the discovery of thiazole-based compounds acting as SIRT2 inhibitors (T1, SIRT2 IC50 = 17.3 µM). Herein, ligand-based approaches followed by molecular docking simulations allowed us to evaluate in silico a novel small series of thiazoles (3a-3d and 5a, 5d) as putative SIRT2 inhibitors. Results from the computational studies revealed comparable molecular interaction fields (MIFs) and docking positionings of most of these compounds with respect to reference SIRT2Is. Biochemical and biological assays validated this study and pointed to compound 5a (SIRT2 IC50 = 9.0 µM) as the most interesting SIRT2I that was worthy of further development as an anticancer agent.

Design, Synthesis of Novel Pyrimidine Derivatives Containing Alkenyl Moieties With Herbicidal Activities

ABSTRACTTo identify lead compounds with potent herbicidal activity, a range of pyrimidine derivatives containing alkenyl groups were designed, synthesized, and characterized using nuclear magnetic resonance (NMR) spectroscopy and high‐resolution mass spectrometry (HRMS). The synthetic pathways for producing these compounds involved substitution reactions, cyclization, hydrolysis, and other processes. The starting materials for each reaction step were readily accessible, facilitating synthesis. The purification of the final product was straightforward, yielding approximately 80%, under mild reaction conditions. Moreover, a pot culture experiment was employed to assess the herbicidal efficacy of the aforementioned compounds. Compounds 6a, 6b, 6h, and 6j demonstrated a significant inhibition against Amaranthus retroflexus, comparable to fomesafen at 150 g a.i./hm2. This suggests that these compounds hold promise as potential lead structures for herbicidal agents. The docking results indicated that the binding energies of compound 6a with protoporphyrinogen oxidase (PPO) were both negative and spontaneous, with numerous interaction active sites. Thus, it is speculated that compound 6a is a PPO inhibitor.