Compounds C1 Research Articles

Impact of Eucalyptus maculata Hook resin exudate constituents on reducing COX-2 gene expression: In-vivo anti-inflammatory, molecular docking and dynamics studies

Ethnopharmacological relevanceEucalyptus maculata Hook from the Myrtaceae family is a native Australian plant that is frequently cultivated in Egypt. Many Eucalyptus species, including E. maculata, were widely used by the Dharawal, the indigenous Australian people, for their anti-inflammatory properties. Aim of the study: The purpose of this study was to determine the anti-inflammatory activity of the ethanol extract of E. maculata resin exudate, its methylene chloride and n-butanol fractions, as well as the isolated compounds. Materials and methods: the ethanol extract was partitioned by methylene chloride, and n-butanol saturated with water. The fractions were chromatographed to isolate pure compounds. In-vivo anti-inflammatory activity of the ethanol extract, the fractions at a dose of 200 mg/kg, and the isolated compounds (20 mg/kg) was estimated using carrageenan-induced rat paws edema method against indomethacin (20 mg/kg). The activity was supported by histopathological and biochemical parameters. Results: Three isolated compounds were identified as aromadendrin (C1), 7-O-methyl aromadendrin (C2), and naringenin (C3). Our findings demonstrated that the tested fractions significantly reduced the paw edema starting from the 3rd to the 5th hour as compared to the positive control, compounds C2 and C3 showed the greatest significant reduction in paw edema. The ethanol extract, fractions, C2, and C3 demonstrated an anti-inflammatory potential through reducing the levels of TNF-α, IL-6, and PGE2, as well as COX-2 protein expression compared to the negative control. These results were supported by molecular docking, which revealed that the isolated compounds had high affinity to target COX-1 and COX-2 active sites with docking scores ranging from −7.3 to −9.6 kcal mol−1 when compared to ibubrofen (−7.8 and −7.4 kcal mol−1, respectively). Molecular dynamics simulations were also performed and confirmed the docking results. Conclusion: The results supported the traditional anti-inflammatory potency of E. maculata Hook, and the biochemical mechanisms underlying this activity were highlighted, opening up new paths for the development of potent herbal anti-inflammatory medicine. Finally, our findings revealed that E. maculata resin constituents could be considered as promising anti-inflammatory drug candidates.

Synthesis and anticancer activity of podophyllotoxin derivatives with nitrogen-containing heterocycles.

Three series of podophyllotoxin derivatives with various nitrogen-containing heterocycles were designed and synthesized. The antitumor activity of these podophyllotoxin derivatives was evaluated in vitro against a panel of human tumor cell lines. The results showed that podophyllotoxin-imidazolium salts and podophyllotoxin-1,2,4-triazolium salts a1-a20 exhibited excellent cytotoxic activity. Among them, a6 was the most potent cytotoxic compound with IC50 values of 0.04-0.29μM. Podophyllotoxin-1,2,3-triazole derivatives b1-b5 displayed medium cytotoxic activity, and podophyllotoxin-amine compounds c1-c3 has good cytotoxic activity with IC50 value of 0.04-0.58μM. Furthermore, cell cycle and apoptosis experiments of compound a6 were carried out and the results exhibited that a6 could induce G2/M cell cycle arrest and apoptosis in HCT-116 cells.

Natural Products-Based Botanical Bactericides Discovery: Novel Abietic Acid Derivatives as Anti-Virulence Agents for Plant Disease Management.

The discovery of natural product-based pesticides is critical for agriculture. In this work, a series of novel tricyclic diterpenoid derivatives decorated with an amino alcohol moiety were elaborately prepared from natural abietic acid, and their antibacterial behavior was explored. Bioassay results indicated that compound C2 exhibited the most promising bioactivity (EC50 = 0.555 μg mL-1) against Xanthomonas oryzae pv. oryzae (Xoo), about 73 times higher than the effect of commercial thiodiazole copper (TC). Results of in vivo bioassays showed that compound C2 displayed significantly higher control of rice bacterial leaf blight (curative activity: 63.8%; protective activity: 58.4%) than TC (curative activity: 43.6%; protective activity: 40.8%), and their bioactivity could be improved maximally 16% by supplementing the auxiliaries. Antibacterial behavior suggested that compound C2 could suppress various virulence factors. Overall, these findings suggested that new botanical bactericide candidates could control intractable plant bacterial diseases by suppressing virulence factors.

Physicochemical properties, drug likeness, ADMET, DFT studies, and in vitro antioxidant activity of oxindole derivatives

Poor pharmacokinetic and safety profiles create significant hurdles in the drug development process. This work focuses on a detailed understanding of drug discovery interplay among physicochemical, pharmacokinetic, toxicity endpoints, and antioxidant properties of oxindole derivatives. DFT compıutations were also performed at B3LYP/6-311G** level to evaluate the physicochemical properties, global reactivity features, and intramolecular interactions. The BOILED-Egg pharmacokinetic model envisaged gastrointestinal absorption, blood-brain barrier penetration, and no interaction with p-glycoprotein for compounds C1 and C2. The physicochemical evaluation revealed that C1 possesses superior drug-like properties fit for oral absorption. Both derivatives were predicted to have high plasma protein binding, efficient distribution, and inhibiting CYP 450 major isoforms but serve as substrates only for a few of them. Both molecules have mild to moderate clearance rates. Out of ten toxicity parameters, only hepatotoxicity was predicted. DFT results implied that the meta position of the -OH group made the possibility of charge transfer greater than -para positioned -OH, due to the ΔNmax (eV) values of molecules C1 and C2 being calculated at 2.596 and 2.477, respectively. Both C1 and C2 exhibited a concentration dependant DPPH and ABTS radical scavenging activity. The chemical structure-physicochemical-pharmacokinetic relationship identified the meta position as the favorite for the electron-withdrawing hydroxyl group. This provides useful insight to medicinal chemists to design 6-chlorooxindole derivatives with an acceptable drug-like and pharmacokinetic property.

Synthesis, Characterization and Preliminary Antimicrobial and Antiinfl ammatory Evaluation of New Ibuprofen Hydrazide Derivatives

Non-steroidal anti-infl ammatory medicines (NSAIDs) are medicines that are distributed widely across the world due to their ability to reduce pain and infl ammation. In order to boost the drug’s effi cacy and reduce its harmful side eff ect like GIT ulcers and bleeding, a newly synthesized series of 25-(1-(4-isobutylphenyl) ethyl)-1,3,4-oxadiazole-2-thiol derivatives compounds (C, C 1-3) were prepared from the reaction of ibuprofen hydrazide with carbon disulfi de followed by reaction with various Aryl/ alkyl halide. All target compounds were tested for antimicrobial effi cacy against various strains of bacteria (G+ve, S. pyrogenes and S. aureus) and (G-ve, E. coli and 1Klebsiella pneumoniae). Additionally, fungus species (Candida albicans). Compound C showed good antimicrobial activity for both bacterial strains. At the same time, Compound C1 have the best ant-bacterial activity compared with other synthesized compounds for1 both (G+ve), and (G-ve) bacteria, and compound C3 was the most aff ected one as antifungal. The compound C2 was with lowest antimicrobial activity. All of the produced compounds were examined for their anti-infl ammatory activity using (egg-white generate edema) and the compounds (C, C1, C3) showed good effi cacy when compared to ibuprofen (stander) FTIR and 1H-NMR spectroscopy were used to analyze all of the fi nal products.

Exploring functional and structural features of chemically related natural prenylated hydroquinone and benzoic acid from Piper crassinervium (Piperaceae) on bacterial peroxiredoxin inhibition.

Multiple drug resistance (MDR) bacterial strains are responsible by 1.2 million of human deaths all over the world. The pathogens possess efficient enzymes which are able to mitigate the toxicity of reactive oxygen species (ROS) produced by some antibiotics and the host immune cells. Among them, the bacterial peroxiredoxin alkyl hydroperoxide reductase C (AhpC) is able to decompose efficiently several kinds of hydroperoxides. To decompose their substrates AhpC use a reactive cysteine residue (peroxidatic cysteine-CysP) that together with two other polar residues (Thr/Ser and Arg) comprise the catalytic triad of these enzymes and are involved in the substrate targeting/stabilization to allow a bimolecular nucleophilic substitution (SN2) reaction. Additionally to the high efficiency the AhpC is very abundant in the cells and present virulent properties in some bacterial species. Despite the importance of AhpC in bacteria, few studies aimed at using natural compounds as inhibitors of this class of enzymes. Some natural products were identified as human isoforms, presenting as common characteristics a bulk hydrophobic moiety and an α, β-unsaturated carbonylic system able to perform a thiol-Michael reaction. In this work, we evaluated two chemically related natural products: 1,4-dihydroxy-2-(3',7'-dimethyl-1'-oxo-2'E,6'-octadienyl) benzene (C1) and 4-hydroxy-2-(3',7'-dimethyl-1'-oxo-2'E,6'-octadienyl) benzoic acid (C2), both were isolated from branches Piper crassinervium (Piperaceae), over the peroxidase activity of AhpC from Pseudomonas aeruginosa (PaAhpC) and Staphylococcus epidermidis (SeAhpC). By biochemical assays we show that although both compounds can perform the Michael addition reaction, only compound C2 was able to inhibit the PaAhpC peroxidase activity but not SeAhpC, presenting IC50 = 20.3 μM. SDS-PAGE analysis revealed that the compound was not able to perform a thiol-Michael addition, suggesting another inhibition behavior. Using computer-assisted simulations, we also show that an acidic group present in the structure of compound C2 may be involved in the stabilization by polar interactions with the Thr and Arg residues from the catalytic triad and several apolar interactions with hydrophobic residues. Finally, C2 was not able to interfere in the peroxidase activity of the isoform Prx2 from humans or even the thiol proteins of the Trx reducing system from Escherichia coli (EcTrx and EcTrxR), indicating specificity for P. aeruginosa AhpC.

Fragment-Based Approaches Identified Tecovirimat-Competitive Novel Drug Candidate for Targeting the F13 Protein of the Monkeypox Virus.

Monkeypox is a serious public health issue in tropical and subtropical areas. Antivirals that target monkeypox proteins might lead to more effective and efficient therapy. The F13 protein is essential for the growth and maturation of the monkeypox virus. F13 inhibition might be a viable therapeutic target for monkeypox. The in silico fragment-based drug discovery method for developing antivirals may provide novel therapeutic options. In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox. These compounds were evaluated to identify the most promising fragments based on binding affinity and pharmacological characteristics. The top hits from the chemical screening were docked into the active site of the F13 protein. Molecular dynamics simulations were performed on the top two probable new candidates from molecular docking. The ligand-enzyme interaction analysis revealed that the C2 ligand had lower binding free energy than the standard ligand tecovirimat. Water bridges, among other interactions, were shown to stabilize the C2 molecule. Conformational transitions and secondary structure changes in F13 protein upon C2 binding show more native three-dimensional folding of the protein. Prediction of pharmacological properties revealed that compound C2 may be promising as a drug candidate for monkeypox fever. However, additional in vitro and in vivo testing is required for validation.

Novel spiro[chromanone-2,4′-piperidine]-4-one derivatives as potential inhibitors of fatty acid synthesis in pathogens: Design, synthesis, and biological evaluation

Bacterial survival depends on membrane lipid homeostasis that enables to regulate lipid composition to adapt and optimize their growth in diverse environments. Therefore, the development of inhibitors that interfere with the bacterial fatty acid synthesis process is considered to be a promising tactic. In this study, 58 novel spirochromanone derivatives were prepared and their structure–activity relationship (SAR) was investigated. The bioassay results showed that all most of the compounds showed excellent biological activities, exampled by compounds B14, C1, B15, and B13, which had outstanding inhibitory activities toward various pathogenic bacteria with EC50 values of 0.78 μg/mL ∼3.48 μg/mL. Preliminary antibacterial behavior was studied by a series of biochemical assays including, but not limited to, fluorescence imaging patterns, GC-MS analysis, TEM images, and fluorescence titration experiments. Notably, compound B14 decreased the lipid content of the cell membrane, and increased cell membrane permeability, thereby destroying the integrity of the bacterial cell membrane. Further qRT-PCR results indicated that compound B14 interfered with the mRNA expression levels of fatty acid synthesis process-related genes including ACC, ACP, and Fab family genes. Herein, we highlight the promising bactericidal skeleton based on the spiro[chromanone-2,4′-piperidine]-4-one as a potential inhibitor of fatty acid synthesis.

Synthesis and Evaluation of some Novel Triazolo-thiadizoles Derivatives as Anti-diabetic Activity

Triazolo-thiodiazole and related fused heterocyclic compounds are of interest as potential bioactive molecules. Triazolo-thiodiazole derivatives have attracted the attention of organic chemists due to their biological and chemotherapeutic significance. Research in the field of anti-mycobacterium, anti-inflammatory and anti-microbial therapies is ongoing and studies are seeking. Therefore, the discovery of new effective anti-mycobacterium, anti-inflammatory and antimicrobial agents is imperative. The literature survey indicates that the fuse ring of triazolo-thiazazole derivatives has proven to be a good bioactive molecule. They showed various biological activities such as antibacterial, antifungal, anti-inflammatory, tubercular, anticancer, anticonvulsant, antioxidant, analgesic. In view of the above facts it was felt that some were interested in triazo- synthesis. All drugs were screened for their anti-diabetic activity with the standard drug Acarbose by an in vitro alpha-amylation method. The compounds C1 and C3 have been shown to have significant anti-diabetic activity.

A new sulfonamide-based chemosensor for potential fluorescent detection of Cu2+ and Zn2+ ions

In recent times, there has been an increased demand in the search for probing materials for numerous substances in the environment such as the detection of metals ions. In this study, a new class of pyrazolyl-sulfonamide derivatives of para-nitroaniline were synthesized following a multistep approach. The ligands and complexes were characterized using NMR spectroscopy, IR spectroscopy, and mass spectrometry. All the compounds C1–C3 were synthesized in very good yields (85%–92%) and their photo-physical properties measured. All the compounds show fluorescence behaviour with emissions within the UV and far visible range with quantum yields between 7.7% and 25.7%. TD-DFT calculations predictions for the electronic transitions present are in good agreement with experimental observations.Fluorescent probing studies conducted on the compounds show that C1–C3 were analytically sensitive and possessed significant selectivity towards Cu2+ (for C3) and Zn2+ (for C1 and C2) ions with detection limits between 0.011 and 0.103 mg/L for Cu2+ ions and 0.002–0.135 mg/L for Zn2+ ions. Overall, C1 was found to be the most sensitive molecule for the metals studied, having good quantum yield and better selectivity for Zn2+ ion compared to Cu2+.

Curcumin-Based Heterocycles: Synthesis, Antimicrobial Genotoxicity and Molecular Docking

Curcumin is a natural compound with numerous biological activities and a precursor for many drugs. Development of a convenient one pot synthetic method for synthesizing curcumin-based diazepines and diazoles having antibacterial activities is focussed in this study. A one pot condensation process was developed for synthesizing a novel class of curcumin-based diazoles and diazepines by reacting curcumin with 2-diamino compounds and hydrazines in presence of sulfuric acid as catalyst. IR and 1H NMR were used to characterize the molecular composition of the synthesized curcumin derivatives. The synthesized derivatives were tested for their in vitro antibacterial efficacy against Gram-negative and Gram-positive bacteria. The MIC concentrations ranged from 1.56 to 200 μg/mL. Ampicillin exhibited synergistic effects with compounds C1, C3, C4 and C8. In the genotoxicity test, compound C3 was found to have no effect on the DNA molecules of E. coli strains, suggesting that it is not mutagenic and/or genotoxic. Compound C2 had the strongest interaction with the investigated protein receptor sites when blind molecular docking was conducted on all compounds. Since both H-donating and H-accepting sites of this molecule interact efficiently during the docking. In addition, absorption, distribution, metabolism and excretion (ADME) study showed that compound C2 do not contradict the Lipinski’s rule of drug likeness and showed a low level of passive human gastrointestinal absorption. The results indicated that C2 could be most promising among the studied compounds.

Quantitative Structure-Activity relationship, Molecular Docking and ADMET Screening of Tetrahydroquinoline Derivatives as Anti-Small Cell Lung Cancer Agents

Lung carcinoma (LC) is responsible for almost one-third of all cancer fatalities worldwide. Tetrahydroquinoline is an organic molecule that is the semi-hydrogenated derivative of quinoline and could be found in several naturally occurring compounds such as flindersine, oricine etc. Some tetrahydroquinoline derivatives with pyrazole and hydrazide moieties were evaluated in silico against A549 (human lung cancer cell lines). The quantitative structural-activity relationship (QSAR) model created was statistically significant with validation metrics of R2 (0.9525), R2adj (0.9314), and CV.R (0.9719). The molecular docking analysis revealed that compound C14 demonstrated the best binding affinity towards the studied protein with binding affinity value of –10.1 kcal mol–1 (4LRM). This is in accordance with the experimental result (IC50 = 0.69). The factors observed for ADME&T correlated well with the factors observed for the referenced drug. This study indicates that compounds C1 and C9 can be further developed as anti-epidermal growth factor receptor (EGFR) compounds. Thus, our findings may open door for the design and development of library of efficient Tetrahydroquinoline-based drug-like compounds as potential anti-LC agents.

New iron(III) complexes with 2-formylpyridine thiosemicarbazones: Synthetic aspects, structural and spectral analyses and cytotoxicity screening against MCF-7 human cancer cells

2-Formylpyridine thiosemicarbazone - iron (III) chelates [FeL2] Cl•2H2O {L = L1 (C1) [HL1 = 4-(4-Nitrophenyl)-1-((pyridin-2-yl)methylene)thiosemicarbazide] and L = L2 (C2) [HL2 = 4-(2,5-Dimethoxyphenyl)-1-((pyridin-2-yl)methylene)thiosemicarbazide]} were prepared. The two ligand anions in each complex resulted in saturation of the iron coordination number and consequently the existence of these complexes as 1:1 electrolytes. As well, the iron in these complexes exhibits low-spin electronic configuration. X-ray crystallography of complex C1 indicated its triclinic crystal system and P 1‾ space group. In addition, it proved the ligation through a thiol sulfur atom and two nitrogen atoms of pyridine and azomethine groups. This is while the presence of two water molecules of crystallization in the complex structure was also indicated. The ligand HL1 was selected for cytotoxicity screening against human MCF-7, A-549, HEPG-2 and HCT-116 cancer cells and the most enhanced activities were detected against the breast cells. Against these cells, the compounds HL1, HL2, C1 and C2 induced cytotoxicity, respectively, with IC50 values of 52.4, 145.4, 34.3 and 62.0 μM. However, against the healthy BHK cells, HL1 and HL2 caused cytotoxicity, respectively, with IC50 values of 54.8 and 110.6 μM and cytotoxicity with percent viabilities of 56.7 and 55.4% of the BHK cells by the complexes (137.4 μM of C1 and 131.9 μM of C2) was determined. These activities against MCF-7 cells are less significant compared with the measured value for doxorubicin. But this standard is more toxic to normal cells than the thiosemicarbazones (IC50 (doxorubicin) = 9.66 μM against MCF-7 cells and 36.42 μM against BHK cells).

Schiff bases complexed with iron and their relation with the life cycle and infection by Schistosoma mansoni.

The trematode Schistosoma mansoni causes schistosomiasis, and this parasite's life cycle depends on the mollusk Biomphalaria glabrata. The most effective treatment for infected people is administering a single dose of Praziquantel. However, there are naturally resistant to treatment. This work has developed, considering this parasite's complex life cycle. The synthetics compound were evaluated: i) during the infection of B. glabrata, ii) during the infection of BALB/c mice, and iii) during the treatment of mice infected with S. mansoni. For the first objective, snails infected with miracidia treated with compounds C1 and C3 at concentrations of 25% IC50 and 50% IC50, after 80 days of infection, released fewer cercariae than the infected group without treatment. For the second objective, compounds C1 and C3 did not show significant results in the infected group without treatment. For the third objective, the mice treated with C3 and C1 reduced the global and differential cell count. The results suggest that although the evaluated compounds do not present schistosomicidal properties when placed in cercariae suspension, they can stimulate an immune reaction in snails and decrease mice's inflammatory response. In general, we can conclude that compound C1 and C3 has an anti-schistosomicidal effect both in the larval phase (miracidia) and in the adult form of the parasite.

Discovery of Aryloxy-, Arylthio-, and Arylamino-Containing Acethydrazides as Fungicidal Agents.

The development of new green fungicides is an effective way to solve the resistance of agricultural pathogens and plays an important role in promoting high-quality and sustainable development of modern agriculture. In this project, a series of aryloxy-, arylthio-, and arylamino-containing acethydrazide derivatives were designed, synthesized, and characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, and high-resolution mass spectrometry (HRMS). The fungicidal bioassays indicated that some compounds showed excellent and broad-spectrum fungicidal activity, and the structure-activity relationship was discussed. The in vivo fungicidal activity demonstrated that compounds C4 and D8 exhibited good preventative effects against Fusarium graminearum infecting wheat leaves, of which the preventative activity of compound D8 was almost equal to that of the positive agents. Transmission electron microscopy (TEM) observation revealed that the plasma membrane in the C4-treated F. graminearum hyphal cells was severely contracted and separated with the cell wall, coupling with the visible lysosomes and the disappeared cytoplasm and organelles, which may be the reasons for the shriveled and even ruptured hyphae observed by scanning electron microscopy (SEM). Subsequently, transcriptomics and metabolomics were performed to further elucidate the fungicidal mechanism. The regulatory networks of differential genes and metabolites in plasma membrane-related sphingolipid metabolism, linoleic acid metabolism, α-linoleic acid metabolism, and arachidonic acid metabolism were constructed and elaborated. Additionally, preliminary investigation of seeding growth suggested that compounds C4 and D8 may have different degrees of influence on the growth indicators of wheat seedlings; however, this effect may be negligible as the plant grows.

Phytochemical, Antimicrobial, Antioxidant, and In Vitro Cytotoxicity Evaluation of Echinops erinaceus Kit Tan

Wild plants are used by many cultures for the treatment of diverse ailments. However, they are formed from mixtures of many wanted and unwanted phytochemicals. Thus, there is a necessity to separate the bioactive compounds responsible for their biological activity. In this study, the chemical composition as well as antimicrobial and cytotoxic activities of Echinops erinaceus Kit Tan (Asteraceae) were investigated. This led to the isolation and identification of seven compounds, two of which are new (erinaceosin C3 and erinaceol C5), in addition to methyl oleate (C1) and ethyl oleate (C2), loliolide (C4), (E)-p-coumaric acid (C6), and 5,7,3`,5`-tetrahydroxy flavanone (C7). The structures of the isolated compounds were elucidated by 1D, 2D NMR, and HR-ESI-MS. The methanol extract showed the highest antimicrobial activity among the tested extracts and fractions. The n-hexane and EtOAc extracts showed remarkable antimicrobial activity against B. subtilus, P. aeruginosa, E. coli, and C. albicans. A cytotoxicity-guided fractionation of the most bioactive chloroform extract resulted in the isolation of bioactive compounds C1/C2, which showed significant cytotoxicity against HCT-116 and CACO2 cell lines (IC50 24.95 and 19.74 µg/mL, respectively), followed by compounds C3 (IC50 82.82 and 76.70 µg/mL) and C5 (IC50 99.09 and 87.27 µg/mL), respectively. The antioxidant activity of the bioactive chloroform fractions was screened. Molecular docking was used to explain the results of the antimicrobial and anticancer activities against five protein targets, including DNA gyrase topoisomerase II, enoyl-acyl carrier protein reductase of S. aureus (FabI), dihydrofolate reductase (DHFR), β-catenin, and human P-glycoprotein (P-gp).

Curcumin based pyrazole-thiazole hybrids as antiproliferative agents: Synthesis, pharmacokinetic, photophysical properties, and docking studies

A series of new curcumin pyrazole-thiazole hybrids (C1-C8) were synthesized and characterized by fundamental spectral analysis. The synthesized compounds were tested for antiproliferative activity against the colorectal cancer cell line (COLO-205), breast cancer cell line (MCF-7), liver cancer cell line (HepG-2), lung cancer cell line (A549), and cervical cancer cell line (HeLa) using cisplatin as a positive control. The compounds C7 (IC50 values of 8.57 ± 1.09 µM for COLO-205, 9.22 ± 0.73 µM for MCF-7, 16.95 ± 1.16 µM for HepG-2, 8.48 ± 1.36 µM for A549, and 7.22 ± 1.08 µM for HeLa), C2, and C5 displayed the most potent antiproliferative activity against the growth of all tested cell lines. For the three compounds (C2, C5, and C7), which were shown to have high in vitro anti-cancer activity, we have carried out a kinase inhibitory assay against the EGFR and HER2, where the compound C7 has exhibited double inhibitory potency towards the EGFR when compared to reference erlotinib. Furthermore, in silico molecular docking studies on EGFR (PDB ID: 4HJ0) and HER2 (PDB ID: 3P0Z) proteins revealed that the potent ligands exhibited higher affinity with an active pocket of receptors showing strong hydrogen bond interactions. The compounds C5 and C2 showed potent antioxidant activity. In addition, the drug-likeness of the hybrids was assessed by predicting their physicochemical, pharmacokinetic (ADME), toxicity profiles, and photophysical properties.

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of New Drugs against Human Topoisomerase I Receptor

Human Topoisomerase I (hTop1p) is a ubiquitous enzyme that relaxes supercoiled DNA through a conserved mechanism involving transient breakage, rotation, and binding. Htop1p is the molecular target of the chemotherapeutic drug camptothecin (CPT). It causes the hTop1p-DNA complex to slow down the binding process and clash with the replicative machinery during the S phase of the cell cycle, forcing cells to activate the apoptotic response. This gives hTop1p a central role in cancer therapy. Recently, two artesunic acid derivatives (compounds c6 and c7) have been proposed as promising inhibitors of hTop1p with possible antitumor activity. We used several computational approaches to obtain in silico confirmations of the experimental data and to form a comprehensive dynamic description of the ligand-receptor system. We performed molecular docking analyses to verify the ability of the two new derivatives to access the enzyme-DNA interface, and a classical molecular dynamics simulation was performed to assess the capacity of the two compounds to maintain a stable binding pose over time. Finally, we calculated the noncovalent interactions between the two new derivatives and the hTop1p receptor in order to propose a possible inhibitory mechanism like that adopted by CPT.

Cytotoxicity Evaluation of Chalcone-Coumarin Conjugates Against A549 Cell Line

Coumarins and chalcones have been molecules of considerable interest amongst medicinal chemists owing to their vivid pharmacological potentials including anticancer. A few coumarin-chalcone conjugates (C1-C5) with good antioxidant potential were evaluated for in vitro cytotoxicity against A549 cell lines using MTT assay. The IC50 of the conjugates was calculated after 24 h of treatment. The compounds C3 and C4 with higher mesomeric effects exhibited by the substituents were found to be possessing significant cytotoxic potential with IC50 values of 22.90 ± 2.1, 26.73 ± 6.6 µM respectively.

Design, synthesis, and biological evaluation of aminopyridine derivatives as novel tropomyosin receptor kinase inhibitors.

Tropomyosin receptor kinase (TRK) is a successful target for the treatment of various cancers caused by NTRK gene fusions. Herein, based on a rational drug design strategy, we designed and synthesized 35 aminopyrimidine derivatives that were shown to be TRKA inhibitors in the enzyme assay, among which compounds C3, C4, and C6 showed potent inhibitory activities against TRKA with IC50 values of 6.5, 5.0, and 7.0 nM, respectively. In vitro antiproliferative activity study showed that compound C3 significantly inhibited the proliferation of KM-12 cellsbut had weak inhibitory effect on MCF-7 cells and HUVEC cells. The preliminary druggability evaluation showed that compound C3 exhibited favorable liver microsomal and plasma stabilitiesand had weak or no inhibitory activity against cytochrome P450 isoforms at 10 µM. Compounds C3, C4, andC6 were also selected for ADME (absorption, distribution, metabolism, and elimination) properties prediction and molecular docking studies. Inhibition experiments showed that compound C3 was not selective for TRK subtypes. All results indicated that compound C3 was a useful candidate for the development of TRK inhibitors.