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Abstract A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors as antidiabetic agents. Chemical structure of all new compounds were confirmed by different spectroscopic methods. The designed compounds were evaluated using a MAK 203 kit as DPP4 inhibitors in comparison with Sitagliptin. The biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety of 6-bromo quinazoline ring had promising inhibitory activity with IC50 = 9.25 ± 0.57 µM. The toxicity test of all compounds confirmed safety profile of them. Kinetic studies showed that compound 9i exhibited a competitive-type inhibition with a Ki value of 12.01 µM. Computational approach supported the rationality of our design strategy, as 9i represented appropriate binding interactions with the active sites of DPP4 target. MD simulation outputs validated the stability of ligand 9i at DPP4 active site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, and theoretical IR spectrum was employed to study the reactivity descriptors of 9i and 9a as the most and least potent compounds respectively. Based on the DFT study, compound 9i was softer and, as a result, more reactive than 9a. Taken together, our results showed the potential of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives as promising candidates for developing some novel DPP4 inhibitors for managing of type 2 diabetes.

Citrus aurantium L. hydrosol extracted by steam distillation from its flowers is a highly consumed herbal product in the Iranian traditional market, widely used as a food flavor and therapeutic food and drinks. This study investigated ten commercial hydrosol samples of C. aurantium flowers produced by conventional extraction methods and industrial processes, as well as a laboratory-prepared control sample. A liquid-liquid extraction method and sonication were used to extract essential oils from commercial hydrosols. Samples were then subjected to GC/MS analysis. ATR-IR spectroscopy was another efficient tool used to analyze hydrosol samples. All HPTLC chromatograms exhibited a close resemblance between samples and controls. The cluster analysis was used to compare the results of GC/MS and IR screening. In the HCA dendrograms derived from the GC/MS data, most of the oil sample profiles were found to be very similar to those of the control. Linalool was the most abundant compound in eight samples and the control. α-Terpineol in all hydrosol samples and geraniol in five samples and control were other marker compounds. Ethyl disulfide, dillapiol, and hotrienol were detected in two samples that have not been reported in previous studies and might have resulted from the addition of other herbal hydrosols. Microbial content and pH values were within permissible limits in all samples, making them safe for oral consumption.

Abstract DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand–protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

Summary: Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be interactively explored online in ProteomicsDB.

Background and aims: Today, due to the increasing use of natural and traditional medicinal products, control and standardization of herbal and traditional medicinal products is very important. As most of the traditional medicinal plants are not scientifically validated, scientific evaluation along with traditional knowledge is essential to obtain effective drugs with significant control over the quality of the product for commercial purpose. In traditional Persian medicine, various forms of medicine including one or a combination of several drugs are mentioned. Coriander Triphala widely prescribed as a purgative, gastrointestinal and mental tonic. Despite the widespread use of this drug, no significant control or standardization and documented pharmacognosy studies have been performed on it. Therefore this study is developed for this purpose. Methods: In this study, the traditional form of Coriander Triphala was prepared based on the pharmaceutics points mentioned in traditional medicine texts and quality control and pharmacognostic studies were performed. The associated fingerprints were performed by gas chromatography–mass spectrometry (GC-MS), and then one of the main components of the product was determined by as gas chromatography-flame ionization detector (GC-FID). Results: The spectrum of essential oils of Coriander Triphala and Coriander had 59.19% and 75.34% linalool, respectively. The microbial assay showed no undesirable results. The IR spectrum of Coriander Triphala at first day and 40 days later differed by 2%. Conclusion: Standardization of the product using GC-FID indicates the presence of 0.172 μg linalool in 100 g the Coriander Triphala product.

Abstract Herein, we reported the synthesis of nineteen novel 1,2,4-triazole derivatives including 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl) propan-1-ones (7a-e), 1-(1,3-diphenylpropan-2-yl)-1H-1,2,4-triazole (8a-c) and 1,4-diphenyl-2-(1H-1,2,4-triazol-1-yl) butane-1,4-diones (10a-k). The structures of these derivatives were confirmed by spectroscopic techniques like IR, 1H-NMR, Mass spectroscopy and Elemental analysis. The cytotoxic activities of the synthesized compounds were evaluated against three human cancer cell lines including MCF-7, Hela and A549 using MTT assay. Compounds 7d, 7e, 10a and 10d showed a promising cytotoxic activity lower than 12 μM against Hela cell line. The safety of these compounds was also, evaluated on MRC-5 as a normal cell line and relieved that most of the synthesized compounds have proper selectivity against normal and cytotoxic cancerous cell lines. Finally, molecular docking studies were also, done to understand the mechanism and binding modes of these derivatives in the binding pocket of aromatase enzyme as a possible target.

Some studies have investigated the potential role of transposable elements (TEs) in COVID-19 pathogenesis and complications. However, to the best of our knowledge, there is no study to examine the possible association of TE expression in cell functions and its potential role in COVID-19 immune response at the single-cell level. In this study, we reanalyzed single-cell RNA seq data of bronchoalveolar lavage (BAL) samples obtained from six severe COVID-19 patients and three healthy donors to assess the probable correlation of TE expression with the immune responses induced by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in COVID-19 patients. Our findings indicate that the expansion of myeloid-derived suppressor cells (MDSCs) may be a characteristic feature of COVID-19. Additionally, a significant increase in TE expression in MDSCs was observed. This upregulation of TEs in COVID-19 may be linked to the adaptability of these cells in response to their microenvironments. Furthermore, it appears that the identification of overexpressed TEs by pattern recognition receptors (PRRs) in MDSCs may enhance the suppressive capacity of these cells. Thus, this study emphasizes the crucial role of TEs in the functionality of MDSCs during COVID-19.

Abstract A series of 2-aryl/alkyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines (S 1 –S 11 ) were synthesized with an eco-friendly and recoverable nanocatalyst (GO-Fe3O4–Ti(IV)) as an efficient magnetic composite. The new nanocatalyst was characterized by FT-IR, XRD and, EDS analysis. A conformable procedure, easy to work up and having a short reaction time with high yields are some advantages of this method. The new catalyst is also thermal-stable, reusable and, environment-friendly. The chemical structures of the synthesized 1,3-oxazine compounds were confirmed by comparing their melting points with those reported in literature. Then, the anticonvulsant activity of these compounds was assessed by the intraperitoneal pentylenetetrazole test (ipPTZ). Compounds S 10 and S 11 displayed considerable activity against chemically-induced seizure tests. The molecular simulation was also done to achieve their binding affinities as γ‐aminobutyric acid A (GABA‐A) receptor agonists as an assumptive mechanism of their anticonvulsant action. The result of molecular studies represented strongly matched with biological activity. Molecular docking simulation of the potent compound ( S 10 ) and diazepam as the positive control was performed and some critical residues like Thr262, Asn265, Met286, Phe289, and Val290 were identified. Based on the anticonvulsant results and also in silico ADME predictions, S 11 can be to become a potential drug candidate as an anticonvulsant agent.

Gastric erosion is a multifactorial etiological disorder. The study aimed to evaluate the therapeutic effect of trifluoperazine (TFP ) on gastric lesioninduced by cold-water stress and ethanol in rats. TFP 5, 10 and 20 mg/kg as well as pantoprazole (20 mg/kg), as the standard treatment, was administered via oral gavage, 1 h before gastric lesion-induced by 50% ethanol (5 ml/kg per oral) or immersion in cold water (20-22 °C) in rats. Animals were anesthetized 1 h after ethanol gavage or 4 h after immersion in cold water. The stomach tissue was removed and allocated for histopathological and biochemical parameters including malondialdehyde (MDA )level, superoxide dismutase (SOD) and catalase (CAT) activity assay. Both models were induced significant increase in MDA level and decrease in SOD and CAT activity. Pre-treatment with TFP at doses of 10 and 20 mg/kg significantly increased the activity of SOD and CAT enzymes and decreased the concentration of MDA in both models. Also, pre-treatment with TFP ameliorated ethanol and cold-water stress-induced damage. TFP demonstrated gastric mucosal protection against oxidative injuries caused by ethanol and cold-water stress because of its antioxidant properties and inhibition of toxic oxidant in the stomach tissues. Please cite this article as: Mohammad Javad Khoshnoud, Marzieh Rashedinia, Majid Keshavarzi, Amir Hosein Sakhteman, Vida Izadi, Amin Derakhshanfar. The therapeutic potential of trifluoperazine against ethanol and cold water stress-induced gastric lesions in rat. Trends in Pharmaceutical Sciences. 2022;8(1):13-24 .doi: 10.30476/TIPS.2021.92622.1112

Abstract A series of symmetrical azine derivatives containing different substituted benzyl moieties were designed, synthesized, and evaluated for their inhibitory activity against tyrosinase. The results showed that compounds 3e, 3f, 3h, 3i, 3j, and 3k possess effective tyrosinase inhibition with IC50 values ranging from 7.30 μM to 62.60 μM. Particularly, compounds 3f displayed around three-fold improvement in the potency (IC50 = 7.30 ± 1.15 μM) compared to that of kojic acid (IC50 = 20.24 ± 2.28 μM) as the positive control. Kinetic study of compound 3f confirmed uncompetitive inhibitory activity towards tyrosinase indicating that it can bind to enzyme–substrate complex. Next, molecular docking analysis was performed to study the interactions and binding mode of the most potent compound 3f in the tyrosinase active site. Besides, the cytotoxicity of 3f, as well as its potency to reduce the melanin content were also measured on invasive melanoma B16F10 cell line. Also, 3f exhibited above 82% cell viability in the A375 cell line at 10 µM. Consequently, compounds 3f could be introduced as a potent tyrosinase inhibitor that might be a promising candidate in the cosmetics, medicine, and food industry.

Attenuate Total Reflectance infrared spectroscopy ATR-IR method is a routine, easy and non-time consuming approach to determine and detect drugs in pharmaceutical samples. In this study, sertraline as a widely used antidepressant drug was mixed with various amounts of tablet matrix excipients (lactose, starch and sodium lauryl sulfate that are common excipients in tablet formulations) and the amount of sertraline was assessed by ATR-IR method. At first, ATR-IR spectra data converted to normal matrix by SNV preprocessing approach and then, related signals were assessed by chemometrics model (Partial least squares discriminant analysis (PLS-DA)) with different variables. PLS-DA is able to analyze highly noisy ATR-IR data and can provide a variety of useful and accurate statistics and predictions. The model was able to determine sertraline amount in précised approach with zero error percentage when the number of the components was 7. As a result, the method was able to predict the sertraline amount and can be used in other applications of drug quantitation.

Citrus aurantium L. hydrosol extracted by steam distillation from its flowers is a highly consumed herbal product in the Iranian traditional market, widely used as a food flavour and therapeutic food and drinks. This study investigated ten commercial hydrosol samples of C. aurantium flowers produced by conventional industrial processes, as well as a laboratory-prepared control sample. A liquid-liquid extraction method and sonication were used to extract essential oils from commercial hydrosols. Samples were then subjected to GC/MS analysis. ATR-IR spectroscopy was another efficient tool used to analyze hydrosol samples. All HPTLC chromatograms exhibited a close resemblance between samples and controls. The cluster analysis was used to compare the results of GC/MS and IR screening. In the HCA dendrograms derived from the GC/MS data, most of the oil sample profiles were found to be very similar to those of the control. Linalool was the most abundant compound in eight samples and the control. α-Terpineol in all hydrosol samples and geraniol in control and five other samples were the marker compounds. Ethyl disul- fide, dillapiol, and hotrienol were detected in two samples that have not been reported in previous studies and might have resulted from the addition of other herbal hydrosols. Microbial content and pH values were within permissible limits in all samples, making them safe for oral consumption. [ABSTRACT FROM AUTHOR]

Abstract Aging is correlated with several complex diseases, including type 2 diabetes, neurodegeneration diseases, and cancer. Identifying the nature of this correlation and treatment of age-related diseases has been a major subject of both modern and traditional medicine. Traditional Persian Medicine (TPM) embodies many prescriptions for the treatment of ARDs. Given that autophagy plays a critical role in antiaging processes, the present study aimed to examine whether the documented effect of plants used in TPM might be relevant to the induction of autophagy? To this end, the TPM-based medicinal herbs used in the treatment of the ARDs were identified from modern and traditional references. The known phytochemicals of these plants were then examined against literature for evidence of having autophagy inducing effects. As a result, several plants were identified to have multiple active ingredients, which indeed regulate the autophagy or its upstream pathways. In addition, gene set enrichment analysis of the identified targets confirmed the collective contribution of the identified targets in autophagy regulating processes. Also, the protein–protein interaction (PPI) network of the targets was reconstructed. Network centrality analysis of the PPI network identified mTOR as the key network hub. Given the well-documented role of mTOR in inhibiting autophagy, our results hence support the hypothesis that the antiaging mechanism of TPM-based medicines might involve autophagy induction. Chemoinformatics study of the phytochemicals using docking and molecular dynamics simulation identified, among other compounds, the cyclo-trijuglone of Juglans regia L. as a potential ATP-competitive inhibitor of mTOR. Our results hence, provide a basis for the study of TPM-based prescriptions using modern tools in the quest for developing synergistic therapies for ARDs.

Background: Gastric ulcer is among the most serious stomach disorder universally. Several effective drugs are employed in the management of this disease, although there have been adverse effects in some cases. The aim of this study was to investigate the effect of nortriptyline to protect against gastric lesions, induced by indomethacin or cold-stress in rats. Methods: Gastric lesions were induced by oral indomethacin (30 mg/kg) or cold-shock at 2-4°C. Animals were pre-treated with 5, 10 or 20 mg/kg nortriptyline. After 4hr of exposure to indomethacin or cold shock, the stomach was removed for histological examinations and the levels of enzymatic and non-enzymatic oxidative stress markers were determined in the tissue samples. Results: The results showed that nortriptyline at 20 mg/kg significantly restored the activity of the oxidative stress markers, such as Superoxide Dismutase (SOD) and Catalase (CAT) enzymes. It also decreased the tissue Malondialdehyde (MDA) concentration. In addition, nortriptyline at 20 mg/kg, ameliorated the gastric tissue damages caused by indomethacin or the cold shock. Conclusion: The results suggest that improvement in gastric mucosal lesions can be mediated by nortriptyline pretreatment, which is likely due to its antioxidant property.

Background and purpose: The aim of this study was to evaluate the in vitro and in vivo anti-Toxoplasma gondii (T. gondii) effect of 5-oxo-hexahydroquinoline compounds. Moreover, molecular docking study of the compounds into the active site of enoyl-acyl carrier protein reductase (ENR) as a necessary enzyme for the vitality of apicoplast was carried out. Experimental approach: A number of 5-oxo-hexahydoquinoline derivatives (Z1-Z4) were synthesized. The T. gondii tachyzoites of RH strain were treated by different concentrations (1-64 μg/mL) of the compounds. The viability of the encountered parasites with compounds was assessed using flow cytometry and propidium iodide (PI) staining. Due to the high mortality effect of Z3 and Z4 in vitro, their chemotherapy effect was assessed by inoculation of tachyzoites to four BALB/c mice groups (n = 5), followed by the gavage of various concentrations of the compounds to the mice. Molecular docking was done to study the binding affinity of the synthesized 5-oxo-hexahydroquinolines into ENR enzyme active site byusing AutoDock Vina® software. Docking was performed by a Lamarckian Genetic Algorithm with 100 runs. Findings / Results: Flow cytometry assay results indicated compounds Z3 and Z4 had relevant mortality effect on parasite tachyzoites. Besides, in vivo experiments were also performed and a partial increase of mice longevity between control and experiment groups was recorded. Molecular docking of Z3 and Z4 in the binding site of ENR enzyme indicated that the compounds were well accommodated within the binding site. Therefore, it could be suggested that these compounds may exert their anti-T. gondii activity through the inhibition of the ENR enzyme. Conclusion and implications: Compounds Z3 and Z4 are good leads in order to develop better anti-T. gondii agents as they demonstrated both in vitro and in vivo inhibitory effects on tachyzoites viability and infection. Further studies on altering the route of administration along with additional pharmacokinetics evaluations are needed to improve the anti-T. gondii impacts of 5-oxo-hexahydroquinoline compounds.

Plants are an indispensable cornerstone of sustainable global food supply. While immense progress has been made in decoding the genomes of crops in recent decades, the composition of their proteomes, the entirety of all expressed proteins of a species, is virtually unknown. In contrast to the model plant Arabidopsis thaliana, proteomic analyses of crop plants have often been hindered by the presence of extreme concentrations of secondary metabolites such as pigments, phenolic compounds, lipids, carbohydrates or terpenes. As a consequence, crop proteomic experiments have, thus far, required individually optimized protein extraction protocols to obtain samples of acceptable quality for downstream analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). In this article, we present a universal protein extraction protocol originally developed for gel-based experiments and combined it with an automated single-pot solid-phase-enhanced sample preparation (SP3) protocol on a liquid handling robot to prepare high-quality samples for proteomic analysis of crop plants. We also report an automated offline peptide separation protocol and optimized micro-LC-MS/MS conditions that enables the identification and quantification of ~10,000 proteins from plant tissue within 6 h of instrument time. We illustrate the utility of the workflow by analyzing the proteomes of mature tomato fruits to an unprecedented depth. The data demonstrate the robustness of the approach which we propose for use in upcoming large-scale projects that aim to map crop tissue proteomes.

Endocrine disrupting compounds (EDCs) are a persistent threat to humans and wildlife due to their ability to interfere with endocrine signaling pathways. Inspired by previous work to improve chemical hazard identification through the use of toxicogenomics data, we developed a genomic-oriented data space for profiling the molecular activity of EDCs in an in silico manner, and for creating predictive models that identify and prioritize EDCs. Predictive models of EDCs, derived from gene expression data from rats (in vivo and in vitro primary hepatocytes) and humans (in vitro primary hepatocytes and HepG2), achieve testing accuracy greater than 90%. Negative test sets indicate that known safer chemicals are not predicted as EDCs. The rat in vivo-based classifiers achieve accuracy greater than 75% when tested for in vitro to in vivo extrapolation. This study reveals key metabolic pathways and genes affected by EDCs together with a set of predictive models that utilize these pathways to prioritize EDCs in dose/time dependent manner and to predict EDC evoked metabolic diseases.

Background: Given the importance of Stachys genus in Iran and their significant biological activity, we collected three species of this plant: St. aucheri Benth., Stachys benthamiana Boiss and St. inflata Benth. from different regions of Iran. We examined the free radical scavenging potential, total phenol content and tyrosinase inhibitory activity of their methanol, methanol 80% and dichloromethane extracts. Materials and Methods: Antioxidant activity and total phenol content of the mentioned extracts were assessed using DPPH and FolinCiocalteu reagent, respectively. The inhibitory activity of the extracts on tyrosinase was also investigated. Results: Total phenol content of different extracts was high in the extracts as 98.5-139.7 mg eq. gallic acid/g in methanol 80% extract, 36.8-54.7 mg eq. gallic acid/g in methanol extract and 17.9-44.9 mg eq. gallic acid/g in dichloromethane extract. Furthermore, their antioxidant activity was correlated with total phenol content of the extracts. Methanol 80% extract had the highest total phenol content and antioxidant activity. Evaluation of the tyrosinase inhibitory potential of the extracts revealed that St.inflata exhibited a considerable inhibitory potential (IC50= 5.4 ± 0.6 µM). Conclusion: It can be concluded that tyrosinase inhibitory activity of Stachys genus might be due to the less polar compounds and these compounds are mostly present in the dichloromethane extract of St. inflatai over St. aucheri and St. benthamiana

Dipeptidyl peptidase IV (DPP-4) is a serine protease that plays a crucial role in glucose metabolism; hence, it is a significant target for type II diabetes mellitus treatment. DPP-4 inhibitors decrease glucose concentrations in such patients by preventing the rapid degradation and thereby lengthening the physiological actions of hypoglycemic incretin hormones. In this study, a structure-based virtual screening strategy was applied to search for novel natural DPP4 inhibitors. From the Supernatural database, 1856 natural structures were picked up and were subjected to molecular docking analysis. Thirteen of them were identified to form more stable complexes than the co-crystallized ligand with the DPP-4 protein. The drug-likeness and pharmacokinetic properties of the top five compounds were also predicted. It was proved that the compounds were compliant with the drug-likeness rules and possess favorable pharmacokinetic properties. The proposed natural compounds can be introduced as potential DPP-4 inhibitors that might be promising leads for further drug development.

Aromatic herbal remedies, hydrosols, and essential oils are widely used for women’s hormonal health. Scientific investigation of their major constituents may prevent unwanted infertility cases, fetal abnormalities, and drug-herb interactions. It also may lead to development of new medications. A list of 265 volatile molecules (mainly monoterpenes and sesquiterpenes) were prepared from a literature survey in Scopus and PubMed (2000-2019) on hydrosols and essential oils that are used for women’s hormonal and reproductive health conditions. The PDB (protein data bank) files of the receptors (136 native PDB files) that involve with oxytocin, progesterone, estrogen, prolactin, acetyl choline, androgen, dopamine, human chorionic gonadotropin, luteinizing hormone, follicle-stimulating hormone, aromatase, and HER2 receptors were downloaded from Protein Data Bank. An in silico study using AutoDock 4.2 and Vina in parallel mode was performed to investigate possible interactions of the ligands with the receptors. Drug likeliness was investigated for the most active molecules using DruLiTo software. Aristola-1(10),8-diene, bergapten (5-methoxypsoralen), α-bergamotene, bicyclogermacrene, α-bisabolol oxide A, α-bisabolone oxide, p -cymen-8-ol, 10-epi elemol, α-elemol, β-eudesmol, 7- epi -β-eudesmol, ficusin, β-humulene, methyl jasmonate, nerolidol, pinocarvone, (+)-spathulenol, and thujone had better interactions with some androgen, aromatase, estrogen, progesterone, HER2, AChR, and/or dopamine receptors. Most of these molecules had an acceptable drug likeliness except for α-bergamotene, bicyclogermacrene, β-humulene, and aristola-1(10),8-diene. Some volatile natural molecules can be considered as lead compound for drug development to treat hormonal conditions.

Herbal medicinal oils and hydrosols are of most useful preparations in folk Persian medicine. Till now no comprehensive evaluation has been performed on the impact of simultaneous extraction or mixing the extracted products on chemical composition profile of those preparations. Current study chemically assesses the impact of two different extraction methods for essential oils (EO) and hydrosols (separated and mixed) on chemical composition and activity. Samples of Mentha spicata L. (MS), Zataria multiflora Boiss. (ZM), Bunium persicum (Boiss.) B.Fedtsch. (BP) and Trachyspermum ammi (L.) Sprague (TA) were subjected to hydrodistillation, either individually or in combination with each other. Hydrosols and EO samples of each plant were mixed to prepared new hydrosol and poly-EO samples mixtures. All samples were injected to GC/MS for analysis. Moreover, anti-microbial activity of EOs and hydrosols were measured by MIC method. ATR-IR spectroscopies were used for recorded finger print from EOs. Carvone, Thymol, Cuminic aldehyde, Thymol were identified as the major constituents of MS, ZM, BP, TA EO samples, respectively. Hydrosol of MS, ZM, BP, and TA revealed to have Piperitenone, Carvacrol, Cuminol and Thymol as main components, respectively. The mixed oil samples, from first part had γ-Terpinene and Carvacrol as major components and hydrosol samples had Thymol as major component, respectively. In mixed oils and hydrosols the major components were γ-Terpinene and Thymol in respective order. This study showed that there were differences between main components, antimicrobial activity, antioxidant and ATR-IR spectroscopy of mixed samples in both preparation methods.

Diaryl urea derivatives have exhibited a broad spectrum of biochemical effects and pharmaceutical applications. Several diaryl urea derivatives such as sorafenib, regorafenib, linifanib, and tivozanib and lenvatinib are in clinical trial or clinical use. Therefore, development of small molecules within the diaryl urea scaffold with the ability of binding to variety of enzymes and receptors in the biological system are an interesting topic for researchers. Sorafenib as a diaryl urea derivative is a well-known anticancer agent. Corresponding to available information about biological activities of quinoxaline moieties, based on sorafenib scaffold, several structures were designed by replacement of pyridyl carboxamide group of sorafenib with quinoxalindione moiety. A total of 14 novel compounds in 7 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected followed by O-arylation of 4-acetamidophenol with 5-chloro-2-nitroaniline to provide 5-(4-acetamidophenoxy)-2-nitroaniline. Reduction of the nitro group of 5-(4-acetamidophenoxy)-2-nitroaniline and cyclization of diamine N-(4-(3,4-diaminophenoxy) phenyl) acetamides with oxalic acid afforded compound N-(4-((2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy)phenyl) acetamides which on deacetylation gave compounds 6-(4-aminophenoxy) quinoxaline-2,3 (1H, 4H)-diones. Then resultant compounds, 6-(4-aminophenoxy) quinoxaline-2,3 (1H, 4H)-diones were reacted by appropriate isocyanates/ carbamates to give the target compounds 1-(4-((2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy)phenyl)-3-phenylureas. The structures of compounds confirmed by proton nuclear magnetic resonance (1H NMR), mass spectrum and Fourier transform infrared (FT-IR).