Compounds 4h Research Articles

Novel N-(3-(1-(4-sulfamoylphenyl)triazol-4-yl)phenyl)benzamide Derivatives as Potent Carbonic Anhydrase Inhibitors with Broad-Spectrum Anticancer Activity: Leveraging Tail and Dual-Tail Approaches.

Carbonic anhydrases (CAs) IX and XII are crucial for the survival and metastasis of solid tumors under hypoxic conditions. We designed compounds 7a-s, integrating triazole and benzenesulfonamide scaffolds known for inhibiting tumor-associated CAs IX/XII. Initial synthesis included compounds 7a-e, followed by diversification with small hydrophobic groups (7f-m) and hydrophilic heterocyclic secondary amines (7n-s). Compounds were evaluated against CA II, IX, and XII to assess activity and selectivity. Chlorinated derivative 7l exhibited the highest efficacy against CA IX (KI = 0.317 μM) and ditrifluoromethylated 7j against CA XII (KI = 0.081 μM). Subsequent testing on 60 cancer cell lines at 10 μM revealed promising anticancer activity, especially for dimethylated derivative 7h (CA IX, KI = 1.324 μM; CA XII, KI = 0.435 μM), with GI50 values ranging from 0.361 to 9.21 μM. Molecular docking analyses elucidated binding mechanisms, highlighting potential inhibitory actions of compound 7h on CAs IX and XII.

Unlocking the Antibacterial Potential of Naphthalimide-Coumarins to Overcome Drug Resistance with Antibiofilm and Membrane Disruption Ability against Escherichia coli.

Resistance by bacteria to available antibiotics is a threat to human health, which demands the development of new antibacterial agents. Considering the prevailing conditions, we have developed a library of new naphthalimide-coumarin moieties as broad-spectrum antibacterial agents to fight against awful drug resistance. Preliminary studies indicate that compounds 8e and 8h display excellent antibacterial activity against Escherichia coli, exceeding the performance of marketed drug amoxicillin. These drug candidates effectively inhibit biofilm formation and disrupt the biofilm virulence factor, which is accountable for the formation of strong biofilm. In addition to this, both compounds exhibit fast bactericidal properties, thus shortening the time of treatment and resisting the emergence of drug resistance for up to 20 passages. Further, biofunctional evaluation reveals that both compounds effectively disrupt the membrane, causing the leakage of cytoplasmic contents and loss in metabolic activity. Both compounds 8e and 8h efficiently induce the ROS, leading to the oxidation of GSH to GSSG, decreasing the GSH activity of the cell, and causing oxidative damage to the cells. Additionally, both compounds effectively bind with DNA to block DNA replication and form supramolecular complexes, thus exhibiting antibacterial activity. Moreover, these compounds readily bind human serum albumin with high binding constants and can be transported to the target site easily. These findings reveal that newly synthesized naphthalimide-coumarin conjugates have the potential to build as potent antibacterial agents and can be used further for clinical trials.

Spiro thiochromene-oxindoles as novel anti-inflammatory agents: design, sustainable synthesis, in vitro and in silico evaluations.

A one-pot, acid-, base-, and metal-free, multicomponent strategy has been developed to synthesize spiro thiochromene-oxindole derivatives as potential anti-inflammatory agents. The synthesized compounds were screened in vitro for their anti-inflammatory activity by inhibiting heat-induced Bovine Serum Albumin (BSA) denaturation assay, revealing moderate to good efficacy. Compounds 4e, 4k, and 4h exhibited the highest activity, inhibiting BSA denaturation by 90.97-95.45% at 800 μg mL-1 concentration with half maximal inhibitory concentration (IC50) values of 127.477 ± 2.285, 190.738 ± 3.561, and 285.806 ± 8.894 μg mL-1, respectively. For mechanistic insights in silico studies were conducted, revealing binding affinities of the active compounds with cyclooxygenase-2 (COX-2) protein, with binding energies of -8.9 kcal mol-1 (4e), -8.7 kcal mol-1 (4k), and -8.6 kcal mol-1 (4h). Bioactivity and pharmacokinetic parameters were further analyzed, encompassing ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics. This study highlights the potential of spiro thiochromene-oxindoles as anti-inflammatory agents, warranting further exploration as potential leads. The synthetic strategy for these target compounds utilizes taurine as an eco-friendly bio-organic catalyst, facilitating an acid-, base-, and metal-free intramolecular C-S and C-C bond formation in aqueous media. The reaction involves a one-pot, three-component Knoevenagel-Thia-Michael cascade between substituted isatins, 1,3-dicarbonyls, and 2-naphthalene thiol. Key features of this green protocol include high yields, cost-efficiency, non-toxicity, atom economy, and acid-, base-, and metal-free synthesis in water. Additionally, the catalyst exhibits excellent reusability, maintaining its activity across three cycles with easy recovery, while product isolation is achieved through simple filtration, eliminating the need for chromatographic purification and organic solvents. These attributes underscore this approach's synthetic and environmental advantages, highlighting its potential for broader application in the development of anti-inflammatory agents.

Synthesis and biological evaluation of novel D-ring fused steroidal N(2)-substituted-1,2,3-triazoles.

In this study, a series of 13 new D-ring fused steroidal N(2)-substituted-1,2,3-triazoles were synthesized, characterized and evaluated for their biological activities. The relative binding affinities of the synthesized compounds for the ligand-binding domains of estrogen receptors α and β, androgen receptor and glucocorticoid receptor demonstrated that androstane derivatives 3a and 3h and estratriene derivative 4e showed highly specific and strong binding affinity for estrogen receptor β, while 3b, 3e, 4a and 4b displayed high binding affinity for the glucocorticoid receptor. The synthesized compounds were tested for their ability to inhibit aldo-keto reductases 1C3 and 1C4 in vitro by monitoring NADPH consumption using fluorescence spectroscopy. The most potent aldo-keto reductase 1C3 inhibitors were compounds 3h (71.17%) and 3f (69.9%). Moreover, a molecular docking study was carried out for compounds 3f and 3h against aldo-keto reductase 1C3 and results showed that compounds 3h and 3f could bind in the same site and orientation as EM1404. However, polar atoms in the triazole group enable additional hydrogen bonding deeper in SP1 with Tyr319, Tyr216 and the NADP+ cofactor, which are not visible in the AKR1C3-EM1404 crystal structure. The synthesized compounds were screened for their anticancer activity against four cancer cell lines. Compound 3f demonstrated moderate toxic effects across various cancer types, while displaying lower toxicity towards the healthy cell line. In summary, our findings indicate that N(2)-substituted-1,2,3-triazoles are high-affinity ligands for estrogen receptor β and glucocorticoid receptor, inhibitors of aldo-keto reductase 1C3 enzyme, and exhibit antiproliferative effects against cancer cells, suggesting that they could serve as scaffolds for anticancer drug development.

Unveiling the potential anticancer activity of new dihydropyrimidines through dual inhibition of EGFR and TrkA: Design, synthesis, and in silico study.

A series of designed scaffold of dihydropyrimidine was synthesized as dual tyrosine kinase targets inhibitors using a multicomponent Biginelli reaction which provided a high atom economy in a single pot reaction. Several 1,4-DHPM hybrids were obtained via alkylation with different chloroacetylamine derivatives. All the synthesized derivatives were screened for their antiproliferative efficacy towards various cancer cell lines (HCT-116, PC-3, and MCF-7) and normal cell line WI-38 using MTT assay. The results indicated that compounds 8h and 8i have the most significant inhibitory effect on all evaluated cancer cell lines, displaying IC50 of 3.94-15.78µM. Also, they demonstrated favorable selectivity towards normal cell lines. Moreover, the most active hybrids 8h and 8i were evaluated for their EGFR and TrkA inhibitory activity. The findings indicated that compound 8h had superior inhibitory activity compared to compound 8i on the targeted kinases, effectively stopping the G1 phase of the MCF-7 cell cycle and encouraging apoptosis. Additionally, the molecular docking studies declared that the most active compounds exhibited a notable binding interaction with the binding site of the target proteins. Furthermore, their physicochemical properties, ADMET profiles, and bioavailability radar plots were predicted and analyzed.

Design, synthesis, biological evaluation and multi spectroscopic studies of novel 2-styrylquinoline-carboxamide derivatives as potential DNA intercalating anticancer agents.

In this study, novel 2-styrylquinoline derivatives possessing a planar aromatic system and a flexible side chain with an amino substituent were designed and synthesized as DNA-intercalating antitumor agents. The cytotoxic activity of the synthesized compounds was evaluated against four cancer cell lines including MCF-7 (breast cancer cells), A549 (lung epithelial cancer cells), HCT116 (colon cancer cells) and normal cell line L929 (mouse fibroblast cell line). The results displayed that the anti-cancer activity of the target quinolines is sensitive to the lipophilic nature of the C-6 and C-7 quinoline substituents. The anticancer activity of most of the target quinolines against MCF-7 and A549 cells was more than those of HCT116. Compound 3h possessing two methyl groups at the C-6 and C-7 of quinoline ring displayed the most cytotoxicity with IC50 value of 5.7µM against A549 cancer cells. Interaction of compound 3h with calf thymus DNA (ctDNA) was investigated by means of UV absorption spectrophotometry, fluorescence spectroscopy, circular dichroism (CD), Resonance light scattering (RLS), viscos metric techniques and also by docking and molecular dynamic studies. RLS intensity, fluorescence quenching of ctDNA and fluorescence quenching EtBr-ctDNA and AO-ctDNA complexes augmented with increasing of compound 3h concentration, significant increasing in viscosity and melting point of ctDNA in the presence of compound 3h, absorbance increasing of ctDNA-compound 3h complex by increasing of NaCl and KI concentrations, higher Ksv value for dsctDNA (3.03×104 M-1) compared to ssctDNA (1.31×104 M-1), circular dichroism (CD) studies, docking and molecular dynamic studies revealed that compound 3h can interact with ctDNA through intercalation into DNA.

Synthesis and antifungal evaluation of new azole derivatives containing 1,2,3-triazole.

Invasive fungal infections caused by C. albicans are becoming increasingly serious and there is an urgent need for exploring new antifungal drugs. In the present work, a series of new azole derivatives containing a 1,2,3-triazole moiety have been prepared, and in vitro antifungal activity have been evaluated. The results revealed that most compounds showed excellent antifungal activity against C. albicans SC5314 and drug-resistant SC5314-FR. In particular, compounds 4h, 4j, 4l, 4s and 4w exhibited better antifungal activity than FLC. The preliminary mechanism study indicated that 4s could damage the integrity of the cell structure, increase the permeability of the cell membrane, and cause the leakage of cell contents of C. albicans. The molecular docking study indicated that 4s showed an obvious binding site with the target CYP51 (PDB ID: 5TL8). Therefore, 4s could be considered as a new antifungal agent targeting CYP51 for further study.

Synthesis, biological evaluation and molecular docking studies of flavonol-3-O-β-D-glycoside as a potential inhibitor of SARS-CoV-2 main protease (3CLpro) in drug development for COVID-19.

The COVID-19 pandemic began in March 2020 and has affected many countries and infected over a million people. It has had a serious impact on people's physical and mental health, daily life and the global economy. Today, many drugs show limited efficacy in the treatment of COVID-19 and studies to develop effective drugs continue. Here, we aim to the synthesise and characterise of the flavonol-3-O-glycoside derivatives, the following and evaluated molecular docking studies with antimicrobial activity, inhibition of SARS-CoV-2 main protease enzyme (3CLpro) and nuclease activity. Molecular docking simulations of the synthesized flavonol-3-O-glycoside derivatives, especially compounds 5a, 5d, 5h, 5i and 5m, showed a stronger interaction with SARS-CoV-2 3CLpro in the active site. Two compounds from the target compounds, 5h and 5m, were found to be specifically effective against M. smegmatis and yeasts. In particular, compounds 5a, 5d, 5h, 5i and 5m, which exhibited high activity against the SARS-CoV-2 main protease enzyme, were found to be effective at low concentrations. We determined the IC50 values for the compounds that showed an inhibitory effect as well as their nuclease activities, which further emphasising the potential of our results. Among these, compound 5d showed a significant competitive inhibitor of 3CLpro. Furthermore, nuclease activity studies identified compound 5d as the most potent. The above results suggest that the flavonol-3-O-glycoside derivatives could be promising new antiviral agents for the development of 3CLpro inhibitors to combat COVID-19.

Unveiling the Cyclopropyl Appended Acyl Thiourea Derivatives as Antimicrobial, α-Amylase and Proteinase K Inhibitors: Design, Synthesis, Biological Evaluation, Molecular Docking, DFT and ADMET Studies.

Acyl thiourea scaffolds are frequently employed in drug development to discern unique and essential therapies for the eradication of the most challenging diseases. Hence, we developed a library of novel cyclopropyl incorporating acyl thiourea derivatives (4a-j) and evaluated their antimicrobial, α-amylase, and proteinase K inhibition potential. Compound (4h) (4-methoxy) demonstrated the strongest α-amylase inhibition (IC50 = 1.572 ± 0.017), while compound (4j) (3,4,5-trimethoxy) exhibited potent proteinase K inhibition (1.718 ± 0.061 μM), comparable to the standard acarbose (IC50 = 1.063 ± 0.013 μM) and phenyl methyl sulfonyl fluoride (IC50 = 0.119 ± 0.014 μM). The unsubstituted compound (4a) emerged as the most potent antifungal agent (17 mm zone of inhibition), outperforming the positive control Terbinafine (zone of inhibition 16 mm). These compounds (4a-j) also displayed moderate antibacterial activity. SAR analysis revealed the influences of various substitutions on the acyl thiourea scaffold. Computational studies, including DFT, molecular docking, and ADMET predictions, supported the biological findings and identified these compounds as promising inhibitors of α-amylase, proteinase K, and microbial pathogens.

Design, Synthesis and Biological Activities of Novel meta-Diamide Compounds Containing 1,2,4-Oxadiazole Group

To discover new bisamide compounds with insecticidal and fungicidal activities, 19 novel cyproflanilide derivatives containing 1,2,4-oxadiazole group were designed and synthesized according to the principle of biologically active factor splicing. Preliminary biological assay data indicated that the majority of target compounds demonstrated significant insecticidal activity against Lepidopteran pests. Meanwhile, compounds 5p and 5q showed 97.22 and 100% lethality against Tetranychus cinnabarinus at 400 mg L-1, which were better than cyproflanilide (41.11% at 400 mg L-1). In addition, it is exciting that we have achieved our initial goals as some of the target compounds exhibited both insecticidal and fungicidal activities. For instance, compounds 5b and 5c showed 59.26 and 74.07% fungicidal activities against Cucumber downy mildew at 400 mg L-1, as well as 100% insecticidal activity against Plutella xylostella and armyworm at 100 mg L-1. Compound 5h showed 100% insecticidal activity against armyworm at 10 mg L-1, and also displayed 66.67% fungicidal activity against Cucumber downy mildew at 400 mg L-1. The inhibition rate of compounds 5l and 5s against Cucumber downy mildew reached 88.89 and 96.30% at 400 mg L-1. This work showed the effectively fungicidal application of 1,2,4-oxadiazole group in bisamide compounds and provides insights for optimal structural design.

Design, Synthesis, and Evaluation of Piperazine‐7‐Deazapurine Based Thiazolidone Derivatives as Novel ROCK Inhibitors

AbstractIn this research journey of exploring ROCK inhibitors, we synthesized a new series of substituted piperazine‐7‐deazapurine‐linked thiazolidone analogs (10a–s) via a five‐step process, and employing sophisticated molecular modeling techniques, optimized the crystal structures of ROCK1 and ROCK2 to evaluate the binding affinities of these compounds. The evaluation of ROCK inhibitory activity demonstrated generally low binding affinities across the series, as reflected in their pIC50 values. Significantly, compound 10h emerged as a potent inhibitor of ROCK1 with an impressive pIC50 value of 6.54. Similarly, compound 10q showed strong inhibitory effects on ROCK2, marked by a pIC50 value of 6.03. Notably compound 10k exhibited a balanced inhibitory on both ROCK isoforms with a pIC50 of 5.24 and 5.31 against ROCK1 and ROCK2 respectively, suggesting its viability for further exploration. This research provides significant insights into the structure activity relationships (SAR) of kinase inhibitors, paving the way for designing more targeted and efficacious therapeutic options for diseases involving ROCK kinases.

Design, synthesis and biological evaluation of truncated 1'-homologated 4'-selenonucleosides as PPARγ/δ dual modulators.

This study explores the synthesis and evaluation of truncated 1'-homologated 4'-selenonucleosides as dual modulators of PPARγ and PPARδ. Starting with d-lyxose, a 4'-selenosugar was synthesized and condensed with a nucleobase via an SN2 reaction, followed by modifications at the C2- and N6-positions, yielding compounds 3a-l. Structure-activity trend analysis identified compound 3h, featuring 2-chloro and N6-3-iodobenzylamine substituents, as a potent PPARγ partial agonist and PPARδ antagonist (PPARγ Ki=2.8μM, PPARδ Ki=43nM). This compound significantly enhanced adiponectin production and promoted adipogenic differentiation in hBM-MSCs. The 4'-seleno substitution preserved ligand functionality while enhancing binding affinity and pharmacological efficacy. In silico docking studies supported these binding affinities, demonstrating optimal binding poses for 3h at both PPARγ and PPARδ. These findings underscore the potential of 4'-selenonucleosides as therapeutic agents for metabolic disorders associated with hypoadiponectinemia, meriting further investigation and clinical development.

Biological evaluation of newly synthesized α-benzyl monoxime thiocarbohydrazide derivatives as an antimicrobial and anticancer agent: In vitro screening and ADMET predictions.

The current comprehensive study showcases a meticulous synthesis of novel class of α-benzilmonoxime thiocarbohydrazide (BMOTC) derivatives, and manifesting their multifaceted potential as antibacterial, antifungal, and anticancer agents. The synthesis of target compounds was performed in three phases using literature methods. In the first step, benzilmonoxime is synthesized using benzil and hydroxyl amine hydrochloride, followed by benzilmonoxime imine using thiocarbohydrazide. The final stage involves combining BMOTC imine with various aldehydes and ketones. The antibacterial and antifungal activities of the synthesized derivatives against five bacterial panels, both Gram-positive and Gram-negative, and one fungal pathogen have been screened. Twelve of the twenty-four synthetic derivatives showed noteworthy activity; eight derivatives exhibited growth inhibition (GI) >73 % against Acinetobacter baumannii, two exhibited GI >95 % against Escherichia coli, and two exhibited GI >93 % against Candida albicans at concentration 32 μg/mL. Further assessment revealed that two derivatives 5v and 5w, exhibited negligible cytotoxicity towards human embryonic kidney cells (HK-293) and human red blood cells (RBC), signifying their promising safety profile at concentration 32 μg/mL (GI against Candida albicans - 97.51 % and 93.71 % respectively). The synthesized compounds were subjected to in vitro cytostatic activity, where a rigorous scrutiny against a diverse panel of NCI 60 cancer cell lines representing various malignancies was carried out. A total of eleven compounds emerged as promising candidates, demonstrating significant growth percent (GP) at a concentration of 10 µM. Notably, compounds 5d, 5h, and 5x, turned up as standout performers, exhibiting potent anticancer activity across multiple cancer types, including colon, CNS, melanoma, and breast cancers. Of particular interest, compound 5d displayed notable antiproliferative effects against leukemia cancer cell lines RPMI-8226 & SR, while maintaining non-cytotoxicity against the same. Compound 5h showcased activity against ovarian, non-small cell lung, and prostate cancers, without inducing cytotoxic effects. Compound 5x demonstrated remarkable anticancer activity against leukemia and breast cancer cell lines, further bolstered by its non-cytotoxic nature. A compelling aspect of this study is the comparative analysis with the established drug molecule sunitinib, revealing that compounds 5d, 5h, and 5x exhibit superior potency. These findings not only highlight the therapeutic potential of the BMOTC derivatives but also underscore their viability as promising candidates for future drug development endeavours. This study serves as a pivotal step towards harnessing the untapped therapeutic potential of BMOTC derivatives in combating microbial infections and advancing cancer therapy.

Synthesis and Biological Evaluation of 5'-Deoxy-adenosine Derivatives as A3 Adenosine Receptor Ligands.

The A3 Adenosine Receptor (A3AR) is an important therapeutic target due to its role in inflammation and immune response regulation. Herein, we synthesized and evaluated 5'-deoxy-adenosine derivatives with oxygen at the 4'-position, comparing them to previously studied 4'-thionucleosides. Compound 1h exhibited the highest binding affinity (K i = 5.9 ± 1.1 nM), consistent with the trend observed in the 4'-thionucleosides. Notably, the 5'-deoxy-adenosine derivatives demonstrated enhanced agonistic activity. Docking studies with compound 1h revealed a shift in binding mode when oxygen replaced sulfur at the 4'-position. The compounds retained strong interactions with critical residues, such as Thr94, even without a hydrogen bond donor at the 5'-position. These results explain the increased agonistic effect observed when the ring heteroatom was changed from sulfur to oxygen.

Molecular modeling studies, in vitro antioxidant and antimicrobial assay and BSA affinity of novel benzyl-amine derived scaffolds as CYP51B inhibitors.

New scaffolds derived from benzylamine were prepared, characterized, and tested for their antimicrobial, antioxidant activities and binding interactions with BSA. Structure-activity relationship analysis revealed that compounds incorporating both benzylamine and quinoline or pyridine moieties (specifically 3a and 3d) demonstrated potent antifungal activity, surpassing that of the standard drug Ketoconazole against Penicillium italicum. Molecular docking studies confirmed significant inhibitory activity against the CYP51B enzyme-an essential component of fungal cell walls. In addition, compounds 3h, 3d and 3b displayed promising DPPH radical scavenging activity, indicating its strong potential as an antioxidant source. Thermodynamic parameters of standard antiradical mechanisms confirmed antiradical capacity expressed via formal hydrogen atom transfer (FHT). The results of spectrofluorometric assays and molecular docking studies on the affinity of the tested compounds for the BSA enzyme confirmed that all compounds show significant binding affinity for active site III, with compound 3d demonstrating the highest binding affinity. Key pharmacokinetic parameters were assessed using ADMET analysis, ensuring the viability of these compounds for potential therapeutic applications.

Design, synthesis, and antiproliferative activity of new 1,2,3-triazole/quinazoline-4-one hybrids as dual EGFR/BRAFV600E inhibitors.

A novel series of 1,2,3-triazole/quinazoline-4-one hybrids (8a-t) were designed and synthesized as dual-targeted antiproliferative agents. Compounds 8a-t were evaluated for their antiproliferative efficacy against a panel of four cancer cell lines. The results indicated that most of the evaluated compounds exhibited strong antiproliferative activity, with 8f, 8g, 8h, 8j, and 8l demonstrating the highest potency. These five compounds were investigated as EGFR and BRAFV600E inhibitors. The in vitro tests showed that compounds 8g, 8h, and 8j are strong antiproliferative agents that might work as dual EGFR/BRAFV600E inhibitors. Compounds 8g and 8h were further examined as activators of caspases 3, 8, and Bax and down-regulators of the anti-apoptotic protein Bcl2. The results indicated that the studied compounds had considerable apoptotic antiproliferative action. The investigation of the cell cycle and apoptosis revealed that compound 8g induces cell cycle arrest during the G1 phase transition. Molecular docking experiments are thoroughly examined to validate the binding interactions of the most active hybrids with the active sites of EGFR and BRAFV600E. The data indicated that the examined compounds can efficiently engage with essential amino acid residues in both kinases.

Design, Synthesis, and Biological Evaluation of New Benzimidazole-1,2,4-Triazole Derivatives as Potential Anticancer Agents.

New series of benzimidazole-1,2,4-triazole derivatives were designed, synthesized, and characterized using 1H-NMR, 13C-NMR, and HRMS. These compounds were evaluated for anticancer activity toward HTB-9 bladder and HT-29 colorectal cancer cell lines. Compounds 7h and 7ı were found to be the most active against HTB-9 cell line, with IC50 6.27 and 6.44 μM, respectively, comparable to positive control cisplatin (IC50 = 11.40 μM). Additionally, in HT-29 cell line, compounds 7a and 7ı exhibited the lowest IC50 values (20.37 and 22.71 μM, respectively), which was higher than those of cisplatin (19.79 μM). All active compounds induced apoptosis and caspase 3/7 activity and reduced the migration ability in both cell lines. Particularly, HT-29 cells treated with compound 7ı exerted a higher apoptotic index than cisplatin-treated cells. Furthermore, compounds 7h and 7ı led to G1 cell cycle arrest of HTB-9, and compounds 7a and 7ı against HT-29 induced S and G1 cell cycle arrest, respectively. In conclusion, the antiproliferative effect of active compounds is associated with the induction of apoptosis through caspase 3/7 activation and cell cycle arrest at different phases in HTB-9 and HT-29 cell lines.

Mollugin Derivatives as Anti-Inflammatory Agents: Design, Synthesis, and NF-κB Inhibition.

Nuclear factor κB (NF-κB) is a key inducible transcription factor that controls a large number of genes involved in inflammatory and immune processes. The entire inflammation-mediated process uses NF-κB as a hub, and inflammatory gene transcription and expression can be decreased by blocking the NF-κB signaling pathway, thereby reducing inflammatory damage. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation. Here, we designed and synthesized 27 mollugin derivatives and evaluated the anti-inflammatory activity against NF-κB transcription. Most of the compounds exhibited potent anti-inflammatory activity, and compound 5k was the most potent with 81.77% inhibition after intraperitoneal administration, which was significantly more potent than mollugin (49.72%), ibuprofen (47.51%), and mesalazine (47.24%). Investigation of the mechanism of action indicated that 5k down-regulated NF-κB expression, possibly by suppressing LPS-induced expression of the p65 protein. ADMET prediction analysis indicated that compounds 5h and 5k showed good pharmacokinetic properties. The relationship between the structures of the synthesized compounds and the NF-κB inhibitory activity was rationalized using molecular docking simulation experiments. Overall, these results provide an initial basis for the development of 5h and 5k as potential anti-inflammatory agents.

Synthesis, Anti-Oomycete and Anti-Fungal Activities of Anhydride Derivatives of Oleanolic Acid.

Oleanolic acid is a pentacyclic triterpenoid extracted and isolated from the fruit of plants in the Ligustrum lucidum Ait. in the family Oleaceae. To discover biorational natural product-based pesticides, a series of oleanolic acid derivatives containing anhydride active skeletons were prepared by ingeniously introducing an active acyloxy group at its C-28 carboxyl position, and their structures were well characterized by 1H-NMR, 13C NMR, HRMS, and m.p. The stereochemical configuration of compound 8 e was confirmed using single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete and anti-fungal agents against two serious agricultural pests, Phytophthora capsici (P. capsici) and Fusarium graminearum (F. graminearum) we assessed. Amongst evaluated compounds, 1) Compounds 8 h and 8 j displayed significant anti-oomycete against P. capsici, with EC50 values of 54.73 and 65.15 mg/L, respectively. 2) The target compounds have obvious selectivity, and their anti-oomycete activity is significantly better than their anti-fungal activity. 3) Interestingly, there are significant differences in the structure-activity relationship of different substituents or the same substituent at different positions anti-oomycete and anti-fungal against P. capsici and F. graminearum, respectively. The study provides an idea for further exploring the bioactivities of 28-acyloxyoleanolic acid derivatives, and develops the application of 28-acyloxyoleanolic acid derivatives containing anhydride in agriculture.

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.