Compounds 4b Research Articles

Synthesis, Molecular Docking Studies and Biological Evaluation of Thiazolyl Hydrazone Derivatives of Chromone-3-carbaldehyde as Potent Anti-Oxidant and Anti-Inflammatory Agents.

A series of 15 thiazolyl hydrazone derivatives of chromone-3- carbaldehyde have been designed and synthesized by the cyclization of thiosemicarbazone derivatives of chromone-3-carbaldehydes with 4'-substituted-2-bromo acetophenones. All these derivatives were evaluated for antioxidant activity by their direct scavenging activity objects to reactive oxygen species such as DPPH, and nitric oxide, as well as in vitro antiinflammatory activity by a protein denaturation method. Most of these synthesized compounds have shown significant antioxidant activity, among which the compounds 5b, 5c, 5e, 5g, and 5j showed very good antioxidant activities in comparison with the standard ascorbic acid. The in vitro anti-inflammatory activity revealed that the compounds 5b, 5g, and 5h possessed significant activity compared to standard diclofenac sodium. Additionally, molecular docking studies of these molecules using ovalbumin as the protein showed remarkable interactions with its active site residues, and the results indicated that the binding mode of these compounds closely resembled that of the reference compound, diclofenac sodium. Thus, these compounds represent an attractive template for the evaluation of new antiinflammatory and antioxidant agents and might be useful for exploring new therapeutic tools.

Synthesis, biological evaluation, docking and molecular dynamics studies of Biginelli-type tetrahydropyrimidine analogues: Antimicrobial, cytotoxicity and antioxidant activity

Tetrahydropyrimidines have a fascinating scaffold that has garnered substantial attention from pharmacists and medicinal chemists. They are heterocyclic compounds used in anti-cancer, anti-microbial, and antioxidants therapies. Herein, a group of tetrahydropyrimidines were provided by using urea, α-ketoacid/β-ketoester, and appropriate aromatic aldehydes. Then, the antioxidant properties of the derivatives were investigated by the DPPH assay. Besides, the cytotoxicity activity of derivatives was evaluated on two MCF-7 and HepG-2 cell lines. The anti-microbial activity of derivatives was also assessed on two positive gram strains, two negative gram strains, and a fungal strain. Derivatives 4a and 4e showed the strongest antioxidant properties, with IC50s of 0.83 and 0.07 mg/mL, respectively. Compounds 4a and 4d were the most potent compounds, with IC50s of 15.81 and 12.34 µM, respectively, on both cancer cell lines. Furthermore, compounds 4b, 4j, and 4i showed the highest anti-microbial activity on S. aureus (MIC = 7.31 µM), B. subtilis (MIC = 10.81 µM), and E. coli (MIC = 11.45 µM), P. aeruginosa (MIC = 8.12 µM), and C. albicans (MIC = 12.03 µM), respectively. Then, the oral bioavailability and pharmacokinetic properties of compounds were predicted. Moreover, the most possible sites of the molecules that are metabolized by the main cytochromes were estimated. Then, the in silico cardiotoxicity and Cyto-safe properties of the compounds were studied. Finally, to determine the stability of the analogues in the Eg5 active site, docking and molecular dynamics simulations were performed.

Curcuminoid Chalcones: Synthesis and Biological Activity against the Human Colon Carcinoma (Caco-2) Cell Line.

There are many current scientific reports on the synthesis of various derivatives modelled on the structure of known small-molecular and natural bioactive compounds. Curcuminoid chalcones are an innovative class of compounds with significant therapeutic potential against various diseases and they perfectly fit into the current trends in the search for new biologically active substances. The aim of this study was to design and synthesise a series of curcuminoid chalcones. The objective of this scientific paper was to synthesise twelve curcuminoid chalcones and confirm their structures using spectral methods. Additionally, the biological activity of three of the synthesised compounds was evaluated using various assays, and their anticancer properties and toxicity were studied. The proposed derivatives were obtained via the Claisen-Schmidt reaction of selected acetophenones and aldehydes in various conditions using both classical methods: the solutions and solvent-free microwave (MW) or ultrasound (US) variants. The most optimal synthetic method for the selected curcuminoid chalcones was the classical Claisen-Schmidt condensation in an alkaline (NaOH) medium. Spectral methods were used to confirm the structures of the compounds. The resazurin reduction assay, caspase-3 activity assay, and RT-qPCR method were performed, followed by measurements of the intracellular reactive oxygen species (ROS) level and the lactate dehydrogenase (LDH) release level. Twelve designed curcuminoid chalcones were successfully synthesized and structurally confirmed by NMR, MS, and IR spectroscopy. Examination of the anticancer activity was carried out for the three most interesting chalcone products. The results suggested that compound 3a increased the metabolism and/or proliferation of the human colon carcinoma (Caco-2) cell line, while compounds 3b and 3f showed significant toxicity against the Caco-2 cell line. Overall, the preliminary results suggested that compound 3b exhibited the most favourable anticancer activity.

A multi-computational and crystallographic investigation for the antibiotic mechanism of two 2,4-bis(4-methoxyphenamino)pyrimidines

2,4-bis(4-methoxyphenamino)pyrimidines are effective anti-bacterial against various bacteria. The compounds 1a and 1b displayed IC50 values of 3µM and 6.1µM, respectively, against Salmonella Typhimurium. The research aims to comprehensively understand the mechanisms of action of these compounds against bacteria using a diverse array of experimental and computational techniques. The findings from the single-crystal X-ray crystallographic investigation reveal several key insights. First, compounds 1a and 1b adopt distinct conformations of the same structure. Second, the amine-pyrimidine resonance is favored over the amine-methoxy aryl resonance. Third, H⸱⸱⸱H, O⸱⸱⸱H, and N⸱⸱⸱H interactions are the primary driver of molecular assembly. Lastly, Van der Waals and hydrophobic interactions significantly influence the crystal architecture and are conformation-dependent. Computational results suggest that, depending upon the molecular volume, both compounds can inhibit SseF with a marginal difference by stable binding with the same conformer observed in the solid state of 1a through hydrophobic interactions due to the presence of electron-rich phenyl rings. The compound 1b exhibited greater structural variability in the binding site compared to 1a, leading to lower stability. Moreover, the higher molecular volume of 1b, attributed to the methyl group, results in its comparatively lesser fitting in the SseF pore compared to 1a.

Tuning the photophysical and NLO properties of β-diketonates derived from coumarin-triphenylamine-chalcones: effect of the BF2 group.

Herein the synthesis of three difluoroboron β-diketonate complexes (7a-c) and one chalcone (7d) with coumarin and triphenylamine fragments is described. The effect of the inclusion of the difluoroboron (BF2) group and a phenyl linker on the photophysical properties, intramolecular charge transfer (ICT) and nonlinear optical (NLO) properties was studied. These dyes exhibited excellent ICT properties due to their A-π-D and D-π-A-π-D type push-pull configuration. Thus, all compounds presented a strong solvatochromism, given the absorption and emission maxima shifted to red because of the increase in the polarity of the medium. In addition to this, 7a-d showed the formation of a twisted intramolecular charge transfer (TICT) state, which quenched fluorescence in polar solvents. Compounds 7a, 7b and 7d exhibited aggregation-induced emission (AIE) in MeCN/H2O mixtures, while 7c did not have this behavior. In addition, all compounds showed emission in the solid state. Using DFT and TD-DFT calculations, the molecular geometries of the ground state S0 and the first excited state S1 were elucidated, which confirmed the formation of a TICT state. Furthermore, the theoretical and experimental absorption electronic transitions were correlated by testing different functionals: B3LYP, CAM-B3LYP, PBE0, wB97XD, HSEH1PBE and M062X. Frontier molecular orbitals (FOMs) and molecular electrostatic potentials (MEPs) supported the ICT from the donor to the acceptor group. The global reactivity descriptors were studied and the NLO properties were predicted by calculating first (βtot) and second-order (γave) hyperpolarizabilities, revealing that 7a-d would present promising NLO behavior.

Chlorine containing tetrahydropyrimidines: Synthesis, characterization, anticancer activity and mechanism of action

The aim of the presented research was to explore anticancer potential of eleven newly synthesized tetrahydropyrimidine derivatives. The compounds were synthesized via Biginelli multicomponent one-pot reaction using different derivatives of vanillin, ethyl 4-chloroacetoacetate and (N-methyl)urea. The cytotoxic effects of the compounds were examined on three human malignant cell lines (HeLa, K562, and MCF7), and normal lung fibroblasts MRC-5. The mechanisms of anticancer activity were examined for two compounds 4a and 4b which showed the strongest and selective cytotoxicity against chronic myelogenous leukaemia K562 cells (IC50 = 1.76 ± 0.09, and.1.66 ± 0.05, respectively). The changes of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were investigated in the K562 cell line, as well as oncomiRNA miR-10b, miR-23a described to have both features, depending on a specific type of malignancy, and miR-34a with mostly described as a tumour suppressor.

Design, Synthesis, Molecular Docking Studies and Antimicrobial Profiling of 7-Nitroquinazoline Derivatives against Staphylococcus aureus (MRSA)

The alarming increase in antibiotic resistance contributes to the growing risk posed by Staphylococcus aureus (MRSA) in the worldwide healthcare sector. To address the challenge, this study designed, synthesized and evaluated novel quinazoline derivatives, specifically 7-nitroquinazolines, for their antimicrobial efficacy against Staphylococcus aureus (MRSA). Molecular docking studies revealed that compounds 8a and 8b exhibited superior binding affinity to the protein 1T2W, with binding energies of -9.6 kcal/mol and -8.8 kcal/mol, surpassing ciprofloxacin. The derivatives demonstrated favourable pharmacokinetic properties, including moderate lipophilicity, optimal polarity and good water solubility. Compound 8b shows a potent minimum inhibitory concentration (MIC) of 31.1 µg/mL against S. aureus (MRSA ATCC6538), outperforming ciprofloxacin. These findings indicate that compound 8b and related derivatives hold promise as novel therapeutic agents against MRSA, warranting further research to combat the growing issue of antibiotic resistance.

Synthesis of the double spiked µ5-sulfide pentanuclear clusters using thermic reactions of Ru3-mercaptopyridine complexes

The treatment of [Ru3(CO)10(μ-dppm)] with 6-methyl-2-mercaptopyridine (1) or 5-trifluoromethyl-2-mercaptopyridine (2) in refluxing THF for 10 h results in the formation of μ5 sulfide-capped pentanuclear clusters [Ru5(CO)11(μ-H)(μ5-S){μ-κ2N,C-NC5H3(R)})(μ-κ2P2-dppm)2] (R = CH3, 3a, 3a'; R=CF3, 3b,3b') respectively. These compounds exhibit unique structural features, with a μ5-S capped binding trinuclear and dinuclear fragments. The mercaptopyridine ligands undergo S-C bond scission, forming an orthometalated pyridine ligand coordinated to a Ru-Ru bond with a concomitant μ-hydride ligand formation. The structures also feature two dppm ligands, one in the Ru-Ru, which bears the μ-H, and the other bridging the Ru-Ru bond with the orthometallated pyridine. In solution, linkage isomers were observed; they differ in the coordination position of the orthometallated pyridine bonded to the same Ru-Ru bond. A single-crystal X-ray diffraction study confirmed the molecular structures of compounds 3a and 3b. NMR, IR, and HRMS were also carried out.

In vitro antiplasmodium and antitrypanosomal activities, β-haematin formation inhibition, molecular docking and DFT computational studies of quinoline-urea-benzothiazole hybrids

Quinoline-urea-benzothiazole hybrids exhibited low to sub-micromolar in vitro activities against the Plasmodium falciparum (P. falciparum) 3D7 chloroquine (CQ)-sensitive strain, with compounds 5a, 5b and 5f showing activities ranging from 0.33 to 0.97 μM. Against the formation of β-haematin, the majority of the tested compounds were comparable to the reference drug, chloroquine (CQ), with compounds 5c (IC50 = 9.55 ± 0.62 μM) and 5h (IC50 = 9.73 ± 1.38 μM), exhibiting slightly better in vitro efficacy than CQ. The hybrids also exhibited low micromolar to submicromolar activities against Trypanosoma brucei brucei, with 5j-5k being comparable to the reference drug, pentamidine. Compound 5b displayed higher in silico binding energy than CQ when docked against P. falciparum dihydroorotate dehydrogenase enzyme. Compounds 5j and 5k showed higher binding energies than pentamidine within the trypanothione reductase enzyme binding pocket. The root means square deviations of the hit compounds 5b, 5j and 5k were stable throughout the 100 ns simulation period. Post-molecular dynamics MMGBSA binding free energies showed that the selected hybrids bind spontaneously to the respective enzymes. The DFT investigation revealed that the compounds have regions that can bind to the electropositive and electronegative sites of the proteins.

Structural, spectroscopic and electrochemical characterizations of new 2,5-bis(phosphoranyl)-3,6-diaminoquinones

Cu(II) catalyzed open air reactions of 2,5-bis(-P(O)R2))-3,6-dichloro-hydroquinones (R = Ph or iPr) with selected primary amines or ammonia proceeded with oxidation of the hydroquinone ring and substitution of chlorines by the amino groups. The products of these reactions were 2,5-bis(-P(O)R2))-3,6-di(-NHR’)-quinones (1a, R = Ph, R′ = Cy; 1b, R = iPr, R′ = Cy; 2a, R = Ph, R′ = –CH(CH2OH)2; 2b, R = iPr, R′ = –CH(CH2OH)2; 3a, R = Ph, R′ = –CH2CH(OH)CH2OH; 3b, R = iPr, R′ = CH2CH(OH)CH2OH; 4a (R = Ph, R′ = H; 4b, R = iPr, R′ = H). They were isolated as bright orange or yellow solids in moderate/good yields. The compounds were characterized by multinuclear (1H,13C,31P) NMR, FT-IR, UV–Vis, high resolution mass-spectrometry, and cyclic voltammetry. Compounds 1b, 2a, 3a and 4a,b were also characterized by single crystal X-ray diffraction methods.

Structurally diversified sesquiterpenoids from Chloranthus henryi and their neuroprotective activities on H2O2 damaged PC12 cells

Fifteen undescribed sesquiterpenoid monomers, including six pairs of sesquiterpenoid enantiomers (1a/1b-3a/3b and 5a/5b-7a/7b) and three analogues (4, 8, and 9), together with two known sesquiterpenoid dimers (10 and 11) were isolated from the whole plant of Chloranthus henryi Hemsl. Their structures were characterized by spectroscopic data analysis, ECD calculations, and single crystal X-Ray diffractions. Compounds 1a and 1b were highly aromatic cadinane-type sesquiterpenoids. At a concentration of 10μM, compounds 8, 10, and 11 exhibited potent neuroprotective activity against H2O2-induced PC12cell damage. Compounds 10 and 11 significantly decreased the level of ROS. In addition, compound 11 increased the levels of p-AMPK, p-SIRT1, and SIRT3 in the H2O2-induced PC12cell damage via activated the AMPK/SIRT signaling pathway.

Uncovering the Potential ofO-Prenylated 3-aryl-benzopyran Derivatives as Osteogenic and Cancer Cell Growth Inhibitory Agents.

Naturally, O-prenylation of 3-aryl-benzopyrans enhances the biological activities of these compounds. In this study, substituted O-prenylated 3-aryl-benzopyrans (21a-c, 22a-c, 23a-c, 24a-c 25a-c, 27 and 28) were synthesized and evaluated for osteogenic and cancer cell growth inhibitory potentials using cell-based in-vitro models. Amongst the target compounds, 21a, 22b, 23c, and 24c showed good osteogenic activity at 1 pM concentration, whereas 26 and 27 showed osteogenic activity at 100pM and 10nM, respectively. Compounds 21a, 22b, and 23c showed good cancer cell growth inhibitory activity against breast cancer cells (MCF-7 and MBA-231). Amongst active compounds, 27 presented the best anticancer activity against MDAMB-231 cells with selectivity towards non-cancerous cells [IC50 3.76 µM with SI 13.3]. The in-silico study of compounds showed their structural complementarities with the LBD of estrogen receptors and compliance with dragability parameters.

Prenylated Flavanone Enantiomers with α-Glucosidase Inhibitory Activity from the Root Bark of Morus alba.

A focused chemical investigation into the polar fractions of a well-known traditional Chinese medicine called Sang-Bai-Pi (the root bark of Morus alba) yielded a panel of prenylated flavanones. The new compounds were identified as four pairs of enantiomers (1a/1b-4a/4b) featuring the same constitution structure, on the basis of HRMS, NMR and ECD analyses. Several previously reported known racemic co-metabolites were also analyzed and separated by HPLC on chiral columns, and the absolute configurations of pure enantiomers were established via ECD technique for the first time. The inhibition of these isolates against the antidiabetic target α-glycosidase was further tested, with most of them showing decent inhibitory activity compared with the positive control acarbose. The interaction mechanism of two selected compounds (3a & 4b) was explored by kinetics experiment, which revealed a mixed type of inhibition pattern toward the enzyme.

Synthesis and Evaluation of Thiazolyl-indole-2-carboxamide Derivatives as Potent Multitarget Anticancer Agents.

Cancer is a complex disease driven by the dysregulation of multiple signaling pathways and cellular processes. The development of compounds capable of exerting multitarget actions against these key pathways involved in cancer progression is a promising therapeutic approach. Here, a series of novel (E/Z)-N-(4-(2-(2-(substituted)hydrazineyl)-2-oxoethyl)thiazol-2-yl)-1H-indole-2-carboxamide derivatives (6a-6z) were designed, synthesized, and evaluated for their biological activity. Compounds 6e, 6i, 6q, 6v, 7a, and 7b exhibited exceptional cytotoxicity against various cancer cell lines, particularly 6i (IC50 = 6.10 ± 0.4 μM against MCF-7 cell lines) and 6v (IC50 = 6.49 ± 0.3 μM against MCF-7 cell lines). These potent compounds inhibited key protein kinases like EGFR, HER2, VEGFR-2, and CDK2, induced cell cycle arrest at the G2/M phase, and promoted apoptosis. Docking studies revealed improved binding affinity of 6i and 6v with target proteins compared to reference drugs. These findings highlight the promising potential of 6i and 6v as multitarget cancer therapeutics deserving further development.

Novel thiazole-based cyanoacrylamide derivatives: DNA cleavage, DNA/BSA binding properties and their anticancer behaviour against colon and breast cancer cells

A novel series of 2-cyano-3-(pyrazol-4-yl)-N-(thiazol-2-yl)acrylamide derivatives (3a–f) were synthesized using Knoevenagel condensation and characterized using various spectral tools. The weak nuclease activity of compounds (3a–f) against pBR322 plasmid DNA was greatly enhanced by irradiation at 365 nm. Compounds 3b and 3c, incorporating thienyl and pyridyl moieties, respectively, exhibited the utmost nuclease activity in degrading pBR322 plasmid DNA through singlet oxygen and superoxide free radicals’ species. Furthermore, compounds 3b and 3c affinities towards calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were investigated using UV–Vis and fluorescence spectroscopic analysis. They revealed good binding characteristics towards CT-DNA with Kb values of 6.68 × 104 M−1 and 1.19 × 104 M−1 for 3b and 3c, respectively. In addition, compounds 3b and 3c ability to release free radicals on radiation were targeted to be used as cytotoxic compounds in vitro for colon (HCT116) and breast cancer (MDA-MB-231) cells. A significant reduction in the cell viability on illumination at 365 nm was observed, with IC50 values of 23 and 25 µM against HCT116 cells, and 30 and 9 µM against MDA-MB-231 cells for compounds 3b and 3c, respectively. In conclusion, compounds 3b and 3c exhibited remarkable DNA cleavage and cytotoxic activity on illumination at 365 nm which might be associated with free radicals’ production in addition to having a good affinity for interacting with CT-DNA and BSA.Graphical

Synthesis and evaluation of the anti-TB activity of novel 7-(2-(4-substituted-phenyl)-4,5-diphenyl-1H-imidazol-1-yl)-4-methyl-2H-chromen-2-one derivatives and their DFT studies for NLO application

A series of novel 7-(2-(4-substituted-phenyl)-4,5-diphenyl-1H-imidazol-1-yl)-4-methyl-2H-chromen-2-one derivatives 5(a-g) have been synthesized and reported as anti-TB activity and non-linear optical applications. The activity results show that compounds 5b, 5c, 5d, 5f, and 5g exhibited excellent efficacy with a MIC value of 3.12 μg/mL, one-fold greater than the reference standard streptomycin (6.26 μg/mL). An in silico molecular docking study was performed against InhA protein and the results were consistent with the experimental results. Computational studies were performed using the DFT method and results reveal that the presence of greater electronegativity atoms increases the HOMO-LUMO energy gap. The NLO properties show that the presence of stronger electron-donating substituents increases the ICT, charge delocalization and β0 values. The NBO analysis shows significant interactions between LP (Lone pair), π* and σ* in compounds account for the high polarization and enhanced NLO activity.

Synthesis, Molecular Docking, and Anticancer Screening of Ester-Based Thiazole Derivatives.

This study investigates the potential of five compounds as novel anticancer agents. We examined their efficacy, mechanisms of action, and impact on various cancer cell lines, through a comprehensive set of experiments. Notably, compound 3e demonstrated superior activity compared to the positive control cisplatin, with a GI50 value of 6.3±0.7 μM against the breast cancer cell line (MCF-7). Compound 3b also displayed remarkable growth inhibition, yielding GI50 values of 8.7±0.2 μM (MCF-7) and 8.9±0.5 μM against the colon cancer cell line (HCT-116). Cell count experiments further confirmed the potent inhibitory effects of compounds 3e, 3b, and 3c on MCF-7 and HCT-116 cell growth. Compound 3e demonstrated a reduction of 55-60 % at GI50 and complete inhibition (100 %) at 2x GI50. Compound 3b exhibited 50-55 % reduction (GI50) and 90-95 % inhibition (2x GI50) in HCT-116 cells. Compound 3c displayed 75-80 % inhibition (2x GI50) and 35-40 % inhibition (GI50) in HCT-116 cells. In-depth mechanistic investigations unveiled valuable insights into the mode of action of compound 3e. The cell-cycle assay demonstrated G2/M phase arrest, DNA damage, and caspase-mediated apoptosis in both MCF-7 and HCT-116 cells. Caspase activation indicated a significant increase in apoptosis following exposure to compound 3e. Furthermore, compound 3e induced reactive oxygen species (ROS) production, influencing HCT-116 and MCF-7 cells differently. Elevated ROS production in HCT-116 cells and distinct effects in MCF-7 cells contribute to a deeper understanding of the cytotoxic mechanisms of compound 3e. Overall, these findings highlight the potential of the investigated compounds, particularly compound 3e, as effective inducers of apoptosis in cancer cells. Mechanistic insights into cell cycle arrest, caspase-mediated apoptosis, and ROS modulation provide a comprehensive understanding of their cytotoxic effects. This study offers significant contribution to the development of promising anticancer agents and their therapeutic applications.

β-enaminoester derivatives exhibit promising in vitro and in silico antiviral potential against Mayaro virus.

Mayaro virus (MAYV) is the causative agent of Mayaro fever, which is characterized mainly by acute fever and long-term severe arthralgia, common manifestations of other arbovirus infections, making the correct diagnosis a challenge. Besides, MAYV infections have been reported in South America, especially in Brazil. However, the lack of vaccines or specific antiviral drugs to control these infections makes the search for new antivirals an urgent need. Herein, we evaluated the antiviral potential of synthetic β-enaminoesters derivatives against MAYV replication and their pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico strategies. For this purpose, Vero cells were infected with MAYV at an MOI of 0.1, treated with compounds (50 µM) for 24h, and virus titers were quantified by plaque reduction assays. Compounds 2b (83.33%) and 2d (77.53%) exhibited the highest activity with inhibition rates of 83.33% and 77.53%, respectively. The most active compounds 2b (EC50 = 18.92 µM; SI > 52.85), and 2d (EC50 = 14.52 µM; SI > 68.87) exhibited higher potency and selectivity than the control drug suramin (EC50 = 38.97 µM; SI > 25.66). Then, we investigated the mechanism of action of the most active compounds. None of the compounds showed virucidal activity, neither inhibited virus adsorption, but compound 2b inhibited virus entry (62.64%). Also, compounds 2b and 2d inhibited some processes involved with the release of new virus particles. Finally, in silico results indicated good ADMET parameters of the most active compounds and reinforced their promising profile as drug candidates against MAYV.

One-pot synthesis and pharmacological evaluation of new quinoline/pyrimido-diazepines as pulmonary antifibrotic agents.

Aim: Pulmonary fibrosis is a life threating disease which requires an immediate treatment and due to the limited medications, this study focused on synthesizing a series of quinoline-based pyrimidodiazepines 4a-f as a novel antifibrotic hit.Materials & methods: The target compounds were synthesized via a one-pot reaction then investigated in a rat model of lung fibrosis induced by bleomycin (BLM).Results: Results revealed significant attenuation of the tested pro-inflammatory cytokines, fibrotic genes and apoptotic markers; however, Bcl-2 was upregulated, indicating a protective effect against fibrosis. Moreover, the molecular docking studies highlighted promising interactions between compounds 4b and 4c and specific amino acids within the protein pockets of caspase-3 (ARG341 and THR177), malondialdehyde (LYS195, LYS118 and ARG188) and TNF-α (SER99 and NME102).Conclusion: Compounds 4b and 4c emerge as promising candidates for further preclinical investigation as pulmonary antifibrotic agents.

Structural simplification of Osimertinib to elaborate new indolyle-pyrimidine-5-carbonitrile derivatives with Anti-proliferative and Anti-SARS-CoV-2 activities assisted by molecular dynamic simulation

Based on the simplicity and modification of the medication osimertinib, two new series of indolyle-pyrimidine-5-carbonitrile scaffolds were created and synthesized with dual action as anti-SARS-Cov-2 and anticancer. The newly created heterocyclic compounds' chemical structures were effectively characterized. With IC50 values of 18.52, 20.89, and 19.85, respectively, compounds 9b, 10, and 15 had inhibitory actions against SARS-CoV-2 when compared to remdesivir and chloroquine, which served as pharmacological controls and had IC50 values of 3.38 μM and 24.9 μM, respectively.Furthermore, compounds 9a and 13 showed anti-proliferative activity against HepG2 cell lines with IC50s of 5.63 μM and 3.06 μM, respectively, in comparison to doxorubicin's IC50 of 7.4 μM. qRT-PCR revealed that HepG2 cells treated with compounds 9a and 13 showed increased p53 expression levels and decreased CDK1 and PI3K expression levels in comparison to doxorubicin. Molecular dynamics simulations of 20 ns duration were performed with PI3Kα, PI3Kγ, and CDK and active compound complexes. The results confirm that compound 13 has the potential to be a therapeutic candidate for additional preclinical and clinical research, as indicated by the molecular docking data.