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A series of phthalazine derivatives have been synthesized using green protocol methods under microwave irradiation. This involved subjecting chlorophthalazine to microwave irradiation and employing various reagents, including hydrazine derivatives, primary and secondary amines, and active methylene, to generate the novel phthalazine derivatives. Subsequently, a comparison was made between the yield percentage and reaction time of the resulting products obtained from conventional methods and those obtained through microwave irradiation. The structures of all new compounds were confirmed by physical properties and spectral analysis. The phthalazine compounds demonstrated significant anticancer activity against three cancer cell lines and showed promising selectivity when compared with doxorubicin. Compound 6 exhibited the best anticancer activity, with IC50 1.739 µM, 0.384 µM, and 1.52 µM against MCF7, HCT116, and HepG2 cell lines, respectively. The docking results confirmed that the drugs exert their activity by inhibiting PARP-1. The binding scores were in accordance with the experimental IC50, with compound 6 exhibiting the best binding score and retaining the essential binding interactions with the active site. The results of our computational research have revealed that our phthalazine compounds possess a unique structure that effectively inhibits PARP-1.

Abstract A series of novel chromone derivatives of (N-(4-oxo-2-(trifluoromethyl)-4H-chromen-6-yl) benzamides) were synthesized by treating 7-amino-2-(trifluoromethyl)-4H-chromen-4-one with K2CO3 and/or NaH, suitable alkyl halides and acetonitrile and/or 1,4-dioxane. The obtained products are in high yields (87 to 96%) with various substituents in short reaction times with no more by-products and confirmed by FT-IR, 1H, and 13C-NMR Spectral data. The in vitro cytotoxic activity was examined against two human cancer cell lines, namely the human lung adenocarcinoma (A-549) and the human breast (MCF-7) cancer cell line. Compound 4h showed promising cytotoxicity against both cell lines with IC50 values of 22.09 and 6.40 ± 0.26 µg/mL respectively, compared to that of the standard drug. We also performed the in vitro antioxidant activity by DPPH radical, hydrogen peroxide, NO scavenging, and total antioxidant capacity (TAC) assay methods, and they showed significant activities. The possible binding interactions of all the synthesized chromone derivatives are also investigated against selective pharmacological targets of human beings, such as HERA protein for cytotoxic activity and Peroxiredoxins (3MNG) for antioxidant activity which showed closer binding free energies than the standard drugs and evidencing the above two types of activities.

Four copper (II) complexes [Cu(L1)2] (1), [Cu(L2)2] (2), [Cu(L3)2] (3) and [Cu(L4)2] (4) with azo linked O,O donar ligands viz 2-hydroxy-5 (phenyldiazenyl)benzaldehyde (HL1), 1-(2-hydroxy-5-(phenyldiazenyl)phenyl)ethanone (HL2), 2-Hydroxy-5-p-tolylazo-benzaldehyde (HL3), 1-(2-Hydroxy-5-p-tolylazo-phenyl)-ethanone (HL4) have been prepared and characterized by different spectroscopy methods and published earlier by our research group. We investigated the interaction of Human Serum Albumin (HSA) with complexes 1–4 under physiological condition in phosphate buffer solution at pH 7.4 using various spectroscopic techniques. The fluorescence titration spectrum disclosed that the complex 1–4 quench the intrinsic fluorescence of HSA robustly through a static quenching mechanism. Binding constants (Kb) and the number of binding sites (n ≈ 1) were evaluated using modified Stern–Volmer equations. Binding constants were found to be 1.9, 6.6, 0.99 and 1.2x 105 (M−1) for complex 1, 2, 3 and 4 respectively. The CD spectra of free HSA and HSA with complexes 1–4 showed that the complexes have negligibleimpact on the secondary structure of HSA as theyremain helical even after the addition of complexes. Molecular docking study was performed to analyse the binding mode of complexes 1-4with HSA. Docking study revealed that hydrophobic and Vander waals interactions were considered to be the main interaction forces involved in the binding of HSA with complexes 1–4.

The investigation employed cyclic voltammetry (CV) assays to assess the scavenging efficacy of two recently developed compounds, namely meso-tetramethophenyl-porphyrin TPPH2(o-methyl) and meso-tetrabiphenyl-porphyrin (TbiPPH2), against the superoxide anion radical ( ). The IC50 values derived from the CV assays indicated significant scavenging activity for both compounds, with TbPPH2 exhibiting superior potency (85.79 ± 0.11 µg ml-1) compared to the standard antioxidant alpha-tocopherol (353.27 ± 3.21 µg ml-1). Additionally, molecular docking simulations elucidated the interaction of the investigated compounds with specific amino acid residues of glutathione reductase through hydrogen bonding and hydrophobic interactions. The in vitro and in silico results were concordant, highlighting TbiPPH2 as the least active compound against glutathione reductase, boasting the highest inhibitory concentration of 0.63 μM and the lowest docking score of -35.36 kJ mol-1, thus positioning it as a promising candidate for antioxidant applications.

An investigation of the potential ornamental plant Ophiorrhiza chinensis H.S. Lo (Rubiaceae) was conducted, which resulted in the discovery of eight structurally diverse compounds, including two triterpenes, two steroids, two anthraquinones, one alkaloid, and one coumarin. These chemical constituents were isolated by repeated column chromatography and identified by analysis of their NMR spectral data. All of these substances were found in this species for the first time, and four of them were first isolated from the genus Ophiorrhiza. The chemotaxonomic importance of these isolates was discussed, indicating four chemotaxonomic markers for O. chinensis. The tyrosinase inhibitory activity of these isolates was evaluated by a colorimetric method. As a result, six phytochemicals demonstrated moderate tyrosinase inhibitory effects with IC50 values ranging from 25.7 μM to 68.1 μM. Moreover, the binding modes between the active compounds and the mushroom tyrosinase were analyzed preliminarily assisted by molecular docking calculations. This study filled up the knowledge gap of the unreported phytochemical and pharmacological profiles of secondary metabolites from the species O. chinensis.

Dimers of dipyridothiazines with an m-xylene moiety are presented in terms of a comparative analysis with anticancer active structural analogs containing a lutidine system. The synthesis of new isomeric dimers was described, the structure of which was confirmed by 1H, 13C and 2D NMR, and HR MS spectroscopic methods. The preliminary prediction of the pharmacological profile using the Way2Drug server indicated the anticancer potential of the tested derivatives. In vitro biological activity tests were performed on a normal skin cell line (HaCaT) and five cancer cell lines, including human primary colon cancer (SW480), human metastatic colon cancer (SW620), human breast adenocarcinoma (MDA-MB-231), human lung carcinoma (A-549), and human glioblastoma (LN-229), which indicated low cytotoxic activity. In order to explain the surprisingly low activity, a comparative structural analysis of the tested analogs compared to the dimers with the lutidine system was performed using quantum mechanics and molecular docking in relation to histone deacetylase. Molecular docking indicated the different binding sites of the analyzed dimers, which explained the differences in the activity.

Introduction: D-pinitol, a naturally occurring inositol, has diverse biological activities like antioxidant, antimicrobial and anticancer activities. This study aimed to evaluate anti-inflammatory effect of d-pinitol in a chick model. Additionally, in silico studies were performed to evaluate the molecular interactions with cyclooxygenase-2 (COX-2).Methods: The tested groups received d-pinitol (12.5, 25, and 50 mg/kg) and the standard drugs celecoxib and ketoprofen (42 mg/kg) via oral gavage prior to formalin injection. Then, the number of licks was counted for the first 10 min, and the paw edema diameter was measured at 60, 90, and 120 min.Results and Discussion: The d-pinitol groups significantly (p < 0.05) reduced the number of paw licks and paw edema diameters, compared to negative control. When d-pinitol was combined with celecoxib, it reduced inflammatory parameters more effectively than the individual groups. The in silico study showed a promising binding capacity of d-pinitol with COX-2. Taken together, d-pinitol exerted anti-inflammatory effects in a dose-dependent manner, possibly through COX-2 interaction pathway.

Green synthesis using L-proline as an organocatalyst is crucial due to its reusability, mild conditions, clean reactions, easy workup, high purity, short reaction times, and high yields. However, existing methods often involve harsh conditions and longer reaction times. In this study, 2-cyano-N’-(2-cyanoacetyl)acetohydrazide (3) was prepared and condensed with various benzaldehyde derivatives to yield 2-cyano-N’-(2-cyano-3-phenylacryloyl)-3-phenylacrylohydrazide derivatives (5a–e, 7a,b) using a grinding technique with moist L-proline. Additionally, three 2-cyano-N’-(2-cyano-3-heterylbut-2-enoyl)-3-heterylbut-2-enehydrazides (9, 11, 13) were synthesized by condensing compound 3 with respective (heteraryl)ketones (8, 10, 12) following the same method. The synthesized compounds were characterized using IR, NMR, and MS spectroscopy. L-proline’s reusability was confirmed for up to four cycles without significant yield loss, showcasing the protocol’s efficiency and sustainability. The new compounds were screened for anticancer activities against the HCT-116 colon carcinoma cell line using the MTT assay. Molecular docking studies revealed the binding conformations of the most potent compounds to the target protein (PDB ID 6MTU), correlating well with in vitro results. In silico ADMET analysis indicated favorable pharmacokinetic properties, highlighting these novel compounds as promising targeted anti-colon cancer agents.

Current study was conducted to assess the effectiveness of the polyphenol trans-ferulic acid (TFA) as an antiemetic agent using in vivo and in silico methods. To evaluate this, we induced emesis in 3-day-old chicks through the oral administration of copper sulfate (CuSO4·5H2O) at a dose of 50 mg/kg. To ascertain the potential antiemetic mechanism of TFA, we employed various reference drugs such as domperidone (6 mg/kg), ondansetron (5 mg/kg), and hyoscine (21 mg/kg) as positive control groups, while the vehicle acted as a negative control group. TFA was administered orally at the doses of 25, 50 and 100 mg/kg body weight. Both the TFA and reference drug provided alone or in combined groups to assess their synergistic or antagonistic activity on the chicks. Molecular docking of TFA and the selected reference drugs was conducted against 5HT3, D2, H1, NK1, and mAChRs (M1-M5) receptors for determining binding affinity to the receptors. Active binding sites and drug-receptor interactions were predicted with the aid of various computational tools. Various pharmacokinetic features and drug-likeness of all the selected ligands were determined through the SwissADME online server. The results suggest that TFA diminishes the mean number of retches and enhances latency in the chicks at lower doses. In the combined drug therapy, TFA exhibited better antiemetic effects with ondansetron and hyoscine. In silico ADME proposed that TFA retains preferable drug-likeness and better pharmacokinetic properties to be a reliable lead. Additionally, TFA revealed the elevated binding affinity against mAChRs and the ligand (TFA) expressed the highest binding affinity (−7 kcal/mol) with the M5 receptor (6OL9). In conclusion, TFA demonstrated mild antiemetic effects in chicks, possibly through the mAChRs interaction pathway.

4-((4-(1-benzyl-2-methyl-4-nitro-1H-imidazole-5-yl)piperazine-1-yl)methyl)-1-substituted-1H-1,2,3-triazole motifs are designed and synthesized via click chemistry. The reaction of 1-(N1-benzyl- 2-methyl-4-nitro-1H-imidazole- 5-yl)-4-(prop-2-yn-1-yl) piperazine 5 as new scaffold with diverse primary azides to selectively produce 1,4-disubstituted-1,2,3-triazoles 9a–k, 10a–c and 11a–q. Physicochemical methods: when 1H NMR, 13C NMR, and HRMS are utilized to fully characterize all synthesized compounds. X-ray structural determination and analysis for compound 9a is also performed. The newly designed chromophores are assessed for their anti-proliferative potency against three selected human cancer cell lines (MCF-7, HepG2, and PC3), and one normal cell line (Dermal/Fibroblast). Compounds 9g and 9k have shown potent activities against the MCF-7 cell line with IC50 values of (2.00 ± 0.03 μM) and (5.00 ± 0.01 μM) respectively. ADMET studies and Molecular docking investigations are performed on the most active hybrid nitroimidazole derivatives 9g and 9k with 4-hydroxytamoxifen (4-OHT) at the human estrogen receptor alpha (hER) during binding active sites to study the ligand–protein interactions and free binding energies at atomic levels. The triazole ring in the 9g derivative forms a hydrogen bond with Asp58 with distance 3.2 Å. And it is found that polar contact with His231 amino acid residue.In silico assessment of the compounds showed very good pharmacokinetic properties based on their physicochemical values, also the ADMET criteria of the most active hybrid systems are within the acceptable range.

The co-localization of the donor and acceptor fluorophores capable of transferring the energy by the Fӧrster mechanism, on the molecular scaffold of amyloid fibrils offers new opportunities not only for refinement of the amyloid detection and structural analysis, but also for designing photonic nanodevices on their basis. The assembly of these systems involves the non-covalent dye-protein interactions which can hardly be characterized in terms of a precise dye location within the fibril structure that is required for fabricating the FRET-based light harvesting systems or photonic nanowires. In view of this, the dye-fibril binding process deserves a detailed in silico study. In the previous molecular docking studies of the FRET donors and acceptors interacting with the insulin model fibrils we considered only one ligand during the simulation procedure. However, the real situation is much more complicated, when the multiple ligands can compete for the same binding site, a direct complexation between the dyes on the fibril scaffold can take place, the spatial distribution of the bound fluorophores can be unfavorable for the energy transfer, etc. In addition, the mutual orientation of the donor and acceptor molecules essentially contribute to the efficiency of the Förster resonance energy transfer (FRET) in the investigated systems. The present study was undertaken to gain molecular docking insight into the binding of the donor (Thioflavin T) and acceptor (Congo Red or a phosphonium dye TDV) fluorophores to the insulin amyloid fibrils using the multiple docking approach. The employed PatcDock and SwissDock webserves provided evidence for the preferable association of all dyes with the fibril grooves. The protein-ligand interaction profiler (PLIP) was employed for analyzing the (InsF + ThT +CR) and (InsF + ThT + TDV) systems. The revealed binding modes and the types of the dye-fibril interactions may be of importance for a more detailed analysis of the FRET process in amyloid systems and may serve as a background for further in silico studies of the cascade FRET on the amyloid fibril scaffold.

A new series of Fe(III), Cr(III), and La(III) mixed-ligand complexes, resulting from the interaction of 2-aminophenol with 2-hydroxy acetophenone (HL1) as primary ligand and L- histidine (L2) as a secondary ligand, has been investigated using various physicochemical studies such as elemental analyses, molar conductivity, magnetic moment, infrared, UV/Vis, 1H NMR, and mass spectroscopic techniques. The microanalytical results indicate that the mixed ligand complexes were designed in a 1:1:1 M ratio. The electronic spectral data indicated that all the synthesized complexes have an octahedral structure. The disc diffusion assay was used to determine the disc inhibition zone (IZ, mm) and minimum inhibitory concentration (MIC, g/mL) of the investigated compounds against the growth of the pathogenic bacterial strains S. aureus, E. faecalis, P. aeruginosa, Klebsiella sp., and E. coli. The MTT test was used to determine the cytotoxicity of these reported compounds against the human hepatocellular liver cancer (HEPG-2) cell lines. The molecular docking study for the compounds against the EGFR tyrosine kinase receptor (PDB code: 1 M17) was conducted to examine the interactions in protein–ligand complexes. Furthermore, the biological activity of the ligand was investigated using quantitative structure–activity relationship studies (QSAR).

Alzheimer’s disease (AD) is a degenerative neurological condition that severely affects the elderly and is clinically recognised by a decrease in cognition and memory. The treatment of this disease has drawn considerable attention and sparked increased interest among the researchers in this field as a result of a number of factors, including an increase in the population of patients over time, a significant decline in patient quality of life, and the high cost of treatment and care. The current work was carried out for the synthesis of benzimidazole-oxazole hybrid derivatives as efficient Alzheimer’s inhibitors and as a springboard for investigating novel anti-chemical Alzheimer’s prototypes. The inhibition profiles of each synthesised analogue against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes were assessed. All the synthesized benzimidazole-based oxazole analogues displayed a diverse spectrum of inhibitory potentials against targeted AChE and BuChE enzymes when compared to the reference drug donepezil (IC50 = 2.16 ± 0.12 M and 4.50 ± 0.11 µM, respectively). The most active AChE and BuChE analogues were discovered to be analogues 9 and 14, with IC50 values of 0.10 ± 0.050 and 0.20 ± 0.050 µM (against AChE) and 0.20 ± 0.050 and 0.30 ± 0.050 µM (against BuChE), respectively. The nature, number, position, and electron-donating and -withdrawing effects on the phenyl ring were taken into consideration when analysing the structure-activity relationship (SAR). Molecular docking studies were also carried out on the active analogues to find out how amino acids bind to the active sites of the AChE and BuChE enzymes that were being studied.

Prunus mahaleb L., also known as white mahaleb, and native to the Kurdistan region of Iraq, has significant nutraceutical and therapeutic ingredients. The seeds are rich in conjugated fatty acids with small quantities of cyanogenic glycosides, coumarin derivatives, and flavonoids. The contents of the seeds were extracted with the Soxhlet apparatus using n-hexane and petroleum ether solvents, separately. Gas chromatography-mass spectrometry (GC-MS) was used to recognize the chemical composition of the compounds. The radical scavenging activity was performed for the total extracts from n-hexane and petroleum ether solvents using 2,2-diphenyl-1 picrylhydrazyl (DPPH) assay and compared with quercetin as a positive control. Furthermore, molecular docking was performed for the identified compounds against five enzymes that have main roles in intracellular oxidation. Afterwards, drug-like properties and bioactivity predictions were applied for all compounds using Molinspiration software. The results showed four phthalate derivatives, six saturated fatty acids (SFAs), five monounsaturated fatty acids (MUFAs), and three polyunsaturated fatty acids (PUFAs). The n-hexane extract showed competitive antioxidant activity with quercetin and the in-silico studies suggested a notable antioxidant activity of the seed oil contents with apparent drug-likeness properties. Further studies are required to separate the extracts, then perform in vitro antioxidant activity on the compounds.

New candidates of N-phenylpyrazoline derivatives were designed combining the Indole moiety to explore its potential as antimicrobial and antioxidant activity. The starting material synthesis was achieved through One-pot three-component reaction; at that point, it was acylated and interacted with various substituted benzaldehydes to result in new chalcones that were later cyclized to N-phenylpyrazoline, through reaction with phenyl hydrazine. The structures of the synthesized compounds were reinforced by their spectral data. The final compounds were screened for antibacterial activity against resistant strains of Staphylococcus aureus and Escherichia coli microorganisms; as a result, it showed that the compounds with methoxy group at position meta and hydroxy at position ortho were the highly active derivatives. Meanwhile, the highly active compound with antifungal activity against C. Albicans, had nitro group at para position. During the evaluation of proton donating antioxidant activity, using DPPH radical scavenging assays method; it was exposed that, the derivatives with highly active antibacterial had the most antioxidant activity. In the final step, the molecular docking study exposed that the compound with highly active antibacterial and antioxidant activity was the most potent derivative. The resulting studies disclosed that the synthesized N-phenylpyrazoline derivatives displayed less specificity than the reference compounds.

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC50 values (0.002 − 0.004 µM) comparing to Staurosporine of IC50; 0.005 μM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC50 range 0.0149 − 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-β, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-β of IC50 values 0.17 × 10−3, 0.07 × 10−3 µM in comparison with the reference drug sorafenib of IC50; 0.28 × 10−3, 0.13 × 10−3 µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells.

In this study, we investigated the antifungal activity of four different chitosan against Sclerotinia sclerotiorum and Fusarium oxysporum f.sp. cucumerinum (FOC). In addition, molecular docking studies of the chitosan compound against plant pathogens have been evaluated. Concentrations of 0.2, 0.3, 0.5, 1 and 2 mg/mL of each chitosan were used. The activity rate increased as the amount of concentration increased. Strong antifungal effects were observed at concentrations of 1 and 2 mg/mL of chitosan used against test fungi. For the first time with this study, the activity of chitosan against F. oxysporum f. sp. cucumerinum and molecular docking studies against both test pathogens were determined.

Ganoderic acid Me (GA-Me) is a natural bioactive compound derived from Ganoderma lucidum. Our present results suggested that GA-Me inhibited proliferation, induced DNA fragmentation and significantly activated caspase-9 and caspase-3 in HCT116 cells. As shown in our previous studies, GA-Me targets several genes to prevent cancer, including colorectal cancer (CRC). Thus, we hypothesized that GA-Me might be a multitarget ligand against cancer. However, its exact mechanism in CRC remains unclear. Here, whole-transcriptome sequencing was employed to assess the long noncoding RNA (lncRNA), circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) profiles of GA-Me-treated HCT116 cells. In total, 1572 differentially expressed (DE) lncRNAs, 123 DEcircRNAs, 87 DEmiRNAs, and 1508 DEmRNAs were identified. DCBLD2 and RAPGEF5 were validated as two core mRNAs in the DElncRNA, DEcircRNA, and DEmiRNA networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed the biological functions and potential mechanisms of TCONS-00008997, XR-925056.2, circRNA-07908, hsa-miR-100-3p, hsa-miR-1257, hsa-miR-3182, NAV3, ADAM20, and STARD4, which were altered after GA-Me treatment. The regulatory relationships of the XR-925056.2-hsa-miR-3182-NAV3/ADAM20/STARD4, circRNA-07908|Chr22:38986298-39025349-hsa-miR-3182-NAV3/ADAM20, ENST00000414039/ENST00000419190-novel874_mature-MMP9 and circRNA-00314|Chr1:35470863-35479212/circRNA-05460|Chr17:72592203-72649268-novel874_mature-MMP9 immune-regulatory networks involved both noncoding RNAs (ncRNAs) and mRNAs. Molecular docking studies showed that Zn2+ and the His201, His205, His211, Glu202, and Ala165 residues of MMP2 contributed to its high affinity for GA-Me. Zn2+ and the Glu402 and Gly186 residues of MMP9 are important for its interaction with GA-Me. Our results suggested and confirmed that GA-Me is a potential multitarget lead compound for CRC treatment with unique polypharmacological advantages.

Abstract Background Analgesic, anti-inflammatory, and sedative drugs are available with potential side effects such as peptic ulcer and addiction among other things. In this regard, research is underway to find safe, effective, and economical drugs free of these side effects. In this study, an isolated natural product from Diospyros lotus, was tested for the aforementioned bioactivities. Objectives To evaluate analgesic, anti-inflammatory, and sedative potential of D. lotus extracts in animal paradigms using BALB/c mice as experimental model. Methods Analgesic, anti-inflammatory and sedative activities of dinaphthodiospyrol G (1) isolated from the chloroform fraction of D. lotus were evaluated using different experimental procedures. Anti-inflammatory effect was evaluated using the carrageenan and histamine-induced paw edema, whereas the antinociceptive effect was quantified by means of the hot plate analgesiometer. On the other hand, the sedative effect was determined using animal assay for screening the locomotors effects of compound 1. Compound 1 was also subjected to molecular modeling studies against cyclooxygenase enzymes. Results Results from this investigation showed that the extract is devoid of anti-inflammatory and antinociceptive potentials but has a significant sedative effect, whereas the tested compound exhibited 55.23 and 78.34% attenuation in paw edema by carrageenan and histamine assays, respectively. A significant (p

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2–20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (KIs; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12–17, and 19–20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27–195 and 3.2–19, respectively, while compounds 12, 14–17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48–158 and 5.4–31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.Highlights Quinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised. The new molecules potently inhibited the hCA isoforms I, II, IV, and IX. Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Compounds 12–17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 12, 14–17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Graphical Abstract Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12–17, and 19–20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12, 14–17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2–13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2–13 with inhibition constants (KIs) ranging from 57.8–740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2–13 with KI values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (KIs ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.

The title compound, C15H22N4O5S, was prepared via alkylation of 3-(chloromethyl)-5-(pentan-3-yl)-1,2,4-oxadiazole in anhydrous dioxane in the presence of triethylamine. The thiadiazine ring has an envelope conformation with the S atom displaced by 0.4883 (6) Å from the mean plane through the other five atoms. The planar 1,2,4-oxadiazole ring is inclined to the mean plane of the thiadiazine ring by 77.45 (11)°. In the crystal, molecules are linked by C—H...N hydrogen bonds, forming chains propagating along the b-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots have been used to analyse the intermolecular contacts present in the crystal. Molecular docking studies were use to evaluate the title compound as a potential system that interacts effectively with the capsid of the Hepatitis B virus (HBV), supported by an experimental in vitro HBV replication model.

Background: Marburg virus disease (MVD) is a hemorrhagic fever that can kill up to 88% of people. It is transmitted through skin contact or mucous membrane in the eyes, nose, or mouth with blood or body fluids such as urine, saliva, sweat, feces, and by object contaminated with body fluids. Despite these facts, no approved vaccine for the eradication of Marburg virus infections has been developed. Methods: This study described a multi epitope-based peptide vaccine against Marburg virus viral protein 35, using several immunoinformatics tools combined with molecular docking and dynamic simulation studies. Results: Utilizing Vaxijen 2.0 server, the V35 protein revealed to be antigenic with a score of 0.4316. Prediction of the T-cell and B-cell epitopes was then conducted. RTFDAFLGV epitope was found to be the most promising one with binding affinity to the highest numbers of MHC I alleles, a positive score in the Class I immunogenicity study and non-allergen. These results were further confirmed by the good interaction of RTFDAFLGV to the groove of HLA-A*02:01 with binding energy of −8.1 kcal/mol. Finally, the vaccine was cloned in silico to ensure its validity and efficiency of expression. Conclusion: To ensure its safety and immunogenic profile, in-vitro and in-vivo bioassays are recommended to confirm these findings.

In this work, experimental spectroscopic and theoretical methods as quantum chemical calculation were performed for 3-chloro-r(2),c(6)-bis(4-fluorophenyl)-3-methylpiperidin-4-one (abbreviated as CFMP). The CFMP was synthesized and analysed using FT-IR, 1H NMR, 13C NMR, and UV–Vis spectroscopy. Standard functional B3LYP/6–311++G(d,p) density functional theory (DFT) calculations were utilized for the CFMP compound. Molecular electrostatic potential, non-linear optical, and natural bond orbital studies were performed. The charge transfer inside the molecule was demonstrated using HOMO-LUMO energy calculations and Mulliken atomic charges. The vibrational frequency was computed using the DFT/B3LYP/6–311++G(d,p) method. The non-covalent interactions were investigated using the Hirshfeld surface analysis. Furthermore, molecular docking was studied to discover novel inhibitors and drugs in treating Alzheimer's diseases. Further, docking studies were performed to predict and describe the interactions of four proteins with the ligand. This result demonstrates that the CFMP has an inhibitor effect against Alzheimer's diseases.

Triazole-based thiosemicarbazone derivatives (6a–u) were synthesized then characterized by spectroscopic techniques, such as 1HNMR and 13CNMR and HRMS (ESI). Newly synthesized derivatives were screened in vitro for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives (except 6c and 6d, which were found to be completely inactive) demonstrated moderate to good inhibitory effects ranging from 0.10 ± 0.050 to 12.20 ± 0.30 µM (for AChE) and 0.20 ± 0.10 to 14.10 ± 0.40 µM (for BuChE). The analogue 6i (IC50 = 0.10 ± 0.050 for AChE and IC50 = 0.20 ± 0.050 µM for BuChE), which had di-substitutions (2-nitro, 3-hydroxy groups) at ring B and tri-substitutions (2-nitro, 4,5-dichloro groups) at ring C, and analogue 6b (IC50 = 0.20 ± 0.10 µM for AChE and IC50 = 0.30 ± 0.10 µM for BuChE), which had di-Cl at 4,5, -NO2 groups at 2-position of phenyl ring B and hydroxy group at ortho-position of phenyl ring C, emerged as the most potent inhibitors of both targeted enzymes (AChE and BuChE) among the current series. A structure-activity relationship (SAR) was developed based on nature, position, number, electron donating/withdrawing effects of substitution/s on phenyl rings. Molecular docking studies were used to describe binding interactions of the most active inhibitors with active sites of AChE and BuChE.

The slow solvent evaporation approach was used to create a single crystal of (C7H6N3O2)2[ZnCl4] at room temperature. Our compound has been investigated by single-crystal XRD which declares that the complex crystallizes in the monoclinic crystallographic system with the P21/c as a space group. The molecular arrangement of the compound can be described by slightly distorted tetrahedral ZnCl42− anionic entities and 5-nitrobenzimidazolium as cations, linked together by different non-covalent interaction types (H-bonds, Cl…Cl, π…π and C–H…π). Hirshfeld’s surface study allows us to identify that the dominant contacts in the crystal building are H…Cl/Cl…H contacts (37.3%). FT-IR method was used to identify the different groups in (C7H6N3O2)2[ZnCl4]. Furthermore, impedance spectroscopy analysis in 393 ≤ T ≤ 438 K shows that the temperature dependence of DC conductivity follows Arrhenius’ law. The frequency–temperature dependence of AC conductivity for the studied sample shows one region (Ea = 2.75 eV). In order to determine modes of interactions of compound with double stranded DNA, molecular docking simulations were performed at molecular level.

Endeavoring to find a new type of antimicrobial agents, a new sequence of bis-Schiff bases and bis-3-cholro-β-lactams are synthesized. An astonishing class of strained compounds is part of the symmetrical bis-Schiff bases that has widespread applications and building blocks for the combination of bis-3-cholro-β-lactams antibiotics. Bis-3-cholro-β-lactams are synthesized through (Staudinger) [2+2] ketene-imine cycloaddition reaction. Structures of the produced compounds are deduced by 1H, 13C-NMR, and FT-IR spectroscopies. All produced compounds are shown moderate to good antimicrobial activity compared to human pathogenic bacteria strains (Escherichia coli and Staphylococcus aureus), also compared to Aspergillus Niger and Trichophyton mentagrophytes fungi through the broth microdilution technique. A molecular docking study is used for showing the active sides and binding affinity of the products with the target proteins or receptors of E. coli (PDB ID: 3GI9).

Nadia Hanafy Metwally,1 Gamal Riad Saad,1 Esraa Azmy Abd El-Wahab21Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt; 2Department of Engineering Mathematics and Physics, Faculty of Engineering Shoubra, Benha UniversityCorrespondence: Nadia Hanafy MetwallyChemistry Department, Faculty of Science, Cairo University, Giza 12613, EgyptEmail nhmmohamed@yahoo.comIntroduction: It is well known that the grafted multiwalled carbon nanotubes (MWCNTs) have antibacterial activity and lower cytotoxicity. Moreover, pyrazole derivatives have a broad spectrum of biological activity due to their fertile template for many medicinal drugs. On view of these findings we report herein the hybridization between MWCNTs and some pyrazole derivatives as antibacterial agents.Materials and methods: Pyrazole and pyrazolone derivatives were grafted onto the surface of carboxylated MWCNTs via the reaction of carboxylated MWCNTs and the diazonium salts of pyrazoles and pyrazolones using mixed acid treatment. The insertion of the pyrazole and pyrazolone moieties was characterized by Fourier transform infrared (FTIR) spectroscopy, energy dispersion spectroscopy, transmission electron microscopy, X-ray diffraction and thermogravimetric (TGA).Results: The results indicate that pyrazole and pyrazolone moieties successfully attached on carboxylated MWCNTs surface. The neat pyrazole and pyrazolone derivatives and their corresponding carbon nanotubes were tested against Staphylococcus aureus, Bacillus subtilus, Escherichia coli, and Candida albicans bacteria, and Aspergillusniger fungi. The results showed that the grafted carbon nanotubes of pyrazole and pyrazolone derivatives have better antimicrobial activity than the neat pyrazole and pyrazolone derivatives. The molecular docking studies were performed on the most potent antimicrobial compounds to investigate the existence of the interactions between the most active inhibitors and Farnesyl pyrophosphate synthase (FPPS).Conclusion: The surface of the carboxylated MWCNTs was successfully grafted with some pyrazole derivatives. The antibacterial activity was investigated for the newly synthesized compounds and indicated that the grafted MWCNTs have good antibacterial activity toward some pathogenic types of bacteria.Keywords: carbon nanotubes, pyrazoles, pyrazolones, grafting, antimicrobial activity, zeta-potential, molecular docking study

The influence of chiral excipient D-chitosan (CS) on the stereoselective release of racemic ketoprofen (rac-KET) microspheres has been investigated in comparison to those microspheres containing individual enantiomers in vitro and in vivo. Stereoselectivity was observed in vitro release test, with R-KET release slightly higher than that of S-KET, especially in 3% rac-KET loading microspheres. Stereoselectivity is dependent on the content of chiral excipient and pH of release medium. A molecular docking study between CS and KET enantiomers further revealed that S-KET has a stronger interaction with CS compared to R-KET. Moreover, the plasma concentration of KET enantiomers in rats shows substantial differences, as the plasma levels of S-KET were higher than those of R-KET. Plasma levels of enantiomers from the R-KET microspheres had similar stereoselectivity as rac-KET microspheres. The S/R ratio of rac-KET microspheres was significantly lower than that of rac-KET suspension (regular-release formulation) (p

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17–23.87 µM, and of DHFR, with IC50 values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.

A new class of triazinoindole-bearing thiosemicarbazides (1−25) was synthesized and evaluated for α-glucosidase inhibitory potential. All synthesized analogs exhibited excellent inhibitory potential, with IC50 values ranging from 1.30 ± 0.01 to 35.80 ± 0.80 μM when compared to standard acarbose (an IC50 value of 38.60 ± 0.20 μM). Among the series, analogs 1 and 23 were found to be the most potent, with IC50 values of 1.30 ± 0.05 and 1.30 ± 0.01 μM, respectively. The structure−activity relationship (SAR) was mainly based upon bringing about different substituents on the phenyl rings. To confirm the binding interactions, a molecular docking study was performed.

A method for the synthesis of 8-fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one has been developed and the electronic and spatial structure of a new biologically active molecule has been studied both theoretically and experimentally. The title compound was crystallized from acetonitrile and the single-crystal X-ray analysis has revealed that it exists in a monoclinic P21/n space group, with one molecule in the asymmetric part of the unit cell, a = 16.366(3) Å, b = 6.0295(14) Å, c = 21.358(4) Å, β = 105.21(2)°, V = 2033.7(7) Å3 and Z = 4. Hirshfeld surface analysis was used to study intermolecular interactions in the crystal. Molecular docking studies have evaluated the investigated compound as a new inhibitor of hepatitis B. Testing for anti-hepatitis B virus activity has shown that this substance has in vitro nanomolar inhibitory activity against Hepatitis B virus (HBV).

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure–activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host–target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

Snakebite envenomations cause severe local tissue necrosis and the venom metalloproteinases are thought to be the key toxins involved. In this study, the ethanolic extract from seed kernels of Thai mango (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent and dose−dependent inhibitory effects on the caseinolytic and fibrinogenolytic activities of Malayan pit viper and Thai cobra venoms in in vitro tests. molecular docking studies revealed that the binding orientations of the phenolic principles were in the binding pockets of snake venom metalloproteinases (SVMPs). The phenolic principles could form hydrogen bonds with the three histidine residues in the conserved zinc−binding motif and could chelate the Zn2+ atom of the SVMPs, which could potentially result in inhibition of the venom enzymatic activities and thereby inhibit tissue necrosis.

The ethanolic extract from seed kernels of Thai mango (MSKE) (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloyl glucopyranose) exhibited dose-dependent inhibitory effects on enzymatic activities of phospholipase A2 (PLA2), hyaluronidase and L-amino acid oxidase (LAAO) of Calloselasma rhodostoma (CR) and Naja naja kaouthia (NK)venoms by in vitro tests. The anti-hemorrhagic and anti-dermonecrotic activities of MSKE against both venoms were clearly supported by in vivo tests. Molecular docking studies indicated that the phenolic molecules of the MSKE could selectively bind to the active sites or their proximity, or modify conserved residues that are critical for the catalysis of PLA2, and selectively bind to the LAAO binding pocket of both CR and NK venoms and thereby inhibit their enzymatic activities. The results imply a potential use of MSKE against snake venoms.

The alcoholic extract from seed kernels of Thai mango (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent, dose-dependent inhibitory effects on tyrosinase with respect to L-DOPA. Molecular docking studies revealed that the binding orientations of the phenolic principles were in the tyrosinase binding pocket and their orientations were located in the hydrophobic binding pocket surrounding the binuclear copper active site. The results indicated a possible mechanism for their anti-tyrosinase activity which may involve an ability to chelate the copper atoms which are required for the catalytic activity of tyrosinase.

A series of 6-amino-4-substituted-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 5a–j were synthesized via one-pot, four-component condensation reactions of aryl aldehydes 1a–j, propanedinitrile (2), hydrazine hydrate (3) and ethyl acetoacetate (4) under solvent-free conditions. We report herein the use of the Brønsted acid ionic liquid (BAIL) triethylammonium hydrogen sulphate [Et3NH][HSO4] as catalyst for this multi-component synthesis. Compared with the available reaction methodology, this new method has consistent advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. Selected synthesized derivatives were evaluated for in vitro anticancer activity against four human cancer cell lines viz. melanoma cancer cell line (SK-MEL-2), breast cancer cell line(MDA-MB-231), leukemia cancer cell line (K-562) and cervical cancer cell line (HeLa). Compounds 5b, 5d, 5g, 5h and 5j exhibited promising anticancer activity against all selected human cancer cell lines, except HeLa. Molecular docking studies also confirmed 5b and 5d as good lead molecules. An in silico ADMET study of the synthesized anticancer agents indicated good oral drug-like behavior and non-toxic nature.

Objectives: The current study aimed at exploring the secondary metabolites content of Erythrina crista-galli aqueous methanol extract and assessing its phytoestrogenic and cytoprotective activities. Methods: Isolation of the compounds was carried out using conventional chromatographic techniques. The structures of the isolated compounds were elucidated based on the UV, NMR spectral data along with their mass-spectrometric analyses. The phytoestrogenic activity was evaluated in-silico and in vitro using the Arabidopsis thaliana pER8: GUS reporter assay and the proliferation-enhancing activity of MCF-7 cells. Key findings: Phytochemical investigation of E. crista-galli aqueous methanol extract resulted in the isolation and identification of five flavonoids. The plant extract and its fractions showed significant estrogenic activities compared to controls. Conclusion: Five flavonoids were identified from E. crista-galli aqueous methanol extract. To the best of our knowledge, among these flavonoids, apigenin-7-O-rhamnosyl-6-C-glucoside was isolated for the first time from nature. Moreover, luteolin-6-C-glucoside was isolated for the first time from this plant. The plant revealed promising phytoestrogenic activities. This gives rationale to some of its pharmacological properties and suggests additional phytoestrogenic effects, which have not been reported yet.