Discovery of Potent Indolyl-Hydrazones as Kinase Inhibitors for Breast Cancer: Synthesis, X-ray Single-Crystal Analysis, and In Vitro and In Vivo Anti-Cancer Activity Evaluation.

According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer statistics continues to rise, it is imperative to explore new avenues in the ongoing battle against this disease. Therefore, a number of new indolyl-hydrazones were synthesized by reacting the ethyl 3-formyl-1H-indole-2-carboxylate 1 with thiosemicarbazide, semicarbazide.HCl, 4-nitrophenyl hydrazine, 2,4-dinitrophenyl hydrazine, and 4-amino-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione to afford the new hit compounds, which were assigned chemical structures as thiosemicarbazone 3, bis(hydrazine derivative) 5, semicarbzone 6, Schiff base 8, and the corresponding hydrazones 10 and 12 by NMR, elemental analysis, and X-ray single-crystal analysis. The MTT assay was employed to investigate the compounds' cytotoxicity against breast cancer cells (MCF-7). Cytotoxicity results disclosed potent IC50 values against MCF-7, especially compounds 5, 8, and 12, with IC50 values of 2.73 ± 0.14, 4.38 ± 0.23, and 7.03 ± 0.37 µM, respectively, compared to staurosproine (IC50 = 8.32 ± 0.43 µM). Consequently, the activities of compounds 5, 8, and 12 in relation to cell migration were investigated using the wound-healing test. The findings revealed notable wound-healing efficacy, with respective percentages of wound closure measured at 48.8%, 60.7%, and 51.8%. The impact of the hit compounds on cell proliferation was assessed by examining their apoptosis-inducing properties. Intriguingly, compound 5 exhibited a significant enhancement in cell death within MCF-7 cells, registering a notable increase of 39.26% in comparison to the untreated control group, which demonstrated only 1.27% cell death. Furthermore, the mechanism of action of compound 5 was scrutinized through testing against kinase receptors. The results revealed significant kinase inhibition, particularly against PI3K-α, PI3K-ß, PI3K-δ, CDK2, AKT-1, and EGFR, showcasing promising activity, compared to standard drugs targeting these receptors. In the conclusive phase, through in vivo assay, compound 5 demonstrated a substantial reduction in tumor volume, decreasing from 106 mm³ in the untreated control to 56.4 mm³. Moreover, it significantly attenuated tumor proliferation by 46.9%. In view of these findings, the identified leads exhibit promises for potential development into future medications for the treatment of breast cancer, as they effectively hinder both cell migration and proliferation.

Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies.

2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 1 was used as the precursor for the synthesis of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2. The latter was alkylated with different alkylating agents to produce the S-alkylated products 3-6. Galactosylation of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2 produces a mixture of S- and N-galactosides 8 and 9. The hydrazide 1 is converted to azide 10, coupled with glycine methyl ester hydrochloride and a set of amines to produce the target coupled amides 11-15. New compounds were assigned using NMR and elemental analysis. Compound 12 had potent cytotoxicity with IC50 values of 0.5 and 5.27 µM against MCF-7 and HepG2 cell lines compared with doxorubicin, which displayed the following IC50: 2.14 and 2.48 µM for the mentioned cell lines, respectively. Regarding the molecular target, compound 12 exhibited potent PIM-1 inhibition activity with 97.5% with an IC50 value of 14.3 nM compared to Staurosporine (96.8%, IC50 = 16.7 nM). Moreover, compound 12 significantly activated apoptotic cell death in MCF-7 cells, increasing the cell population by total apoptosis by 33.43% (23.18% for early apoptosis and 10.25% for late apoptosis) compared to the untreated control group (0.64%), and arresting the cell cycle at S-phase by 36.02% compared to control 29.12%. Besides, compound 12 caused tumor inhibition by 42.1% in solid tumors in the SEC-bearing mice. Results disclosed that compound 12 significantly impeded cell migration and cell proliferation by interfering with PIM-1 enzymatic activity via considerable apoptosis-induction, which made it an attractive lead compound for the development of chemotherapeutics to treat breast cancer.

Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells.

Cancer is the most severe disease worldwide. Every year, tens of millions of people are diagnosed with cancer, and over half of those people will ultimately die from the disease. Hence, the discovery of new inhibitors for fighting cancer is necessary. As a result, new indolyl-triazole hybrids were synthesized to target breast and liver cancer cells. The synthetic strategy involves glycosylation of the 4-aryltriazolethiones 3a-b with acetyl-protected α-halosugars in the presence of K2CO3 in acetone to give a mixture of ß-S-glycosides 6a-b, 7a-b, and ß-N-glycosides 8a-b, 9a-b. Chemo-selective S-glycosylation was achieved using NaHCO3 in ethanol. The migration of glycosyl moiety from sulfur to nitrogen (S → N glycosylmigration) was achieved thermally without any catalyst. Alkylation of the triazole-thiones with 2-bromoethanol and 1-bromopropan-2-ol in the presence of K2CO3 yielded the corresponding S-alkylated products. The synthesized compounds were tested for their cytotoxicity using an MTT assay and for apoptosis induction targeting PARP-1 and EGFR. Compounds 12b, 13a, and 13b exhibited cytotoxic activities with promising IC50 values of 2.67, 6.21, 1.07 µM against MCF-7 cells and 3.21, 8.91, 0.32 µM against HepG2 cells compared to Erlotinib (IC50 = 2.51, 2.91 µM, respectively) as reference drug. Interestingly, compounds 13b induced apoptosis in MCf-7 and HepG2 cells, arresting the cell cycle at the G2/M and S phases, respectively. Additionally, the dual enzyme inhibition seen in compound 13b against EGFR and PARP-1 is encouraging, with IC50 values of 62.4 nM compared to Erlotinib (80 nM) and 1.24 nM compared to Olaparib (1.49 nM), respectively. The anticancer activity was finally validated using an in vivo SEC-cancer model; compound 13b improved both hematological and biochemical analyses inhibiting tumor proliferation by 66.7% compared to Erlotinib's 65.7%. So, compound 13b may serve as a promising anticancer activity through dual PARP-1/EGFR target inhibition.

Comparison of Machine Learning Techniques for Activities of Daily Living Classification with Electromyographic Data.

Advances in data science and wearable robotic devices present an opportunity to improve rehabilitation outcomes. Some of these devices incorporate electromyography (EMG) electrodes that sense physiological patient activity, making it possible to develop rehabilitation systems able to assess the patient's progress when performing activities of daily living (ADLs). However, additional research is needed to improve the ability to interpret EMG signals. To address this issue, an off-line classification approach for the 26 upper-limb ADLs included in the KIN-MUS UJI dataset is presented in this paper. The ADLs were performed by 22 subjects, while seven EMG signals were recorded from their forearms. From variable-length EMG time windows, 18 features were computed, and 13 features more were extracted from frequency domain windows. The classification performance of five different machine learning techniques, including Support Vector Machines (SVM), Convolutional Neural Networks (CNN), Gated Recurrent Unit (GRU) network, XGBoost, and Random Forests, were compared. CNN performed best amongst individual models, with an accuracy above 80%, compared to SVM with 77%, GRU with 73.9%, and the tree-based models below 64%. Ensemble learning with four CNN models achieved an even higher accuracy of 86%. These results suggest that the CNN ensemble model is capable of classifying EMG signals for most ADLs, which could be used in off-line quantitative assessment of robotic rehabilitation outcomes.

Exploration of novel VEGFR2 tyrosine kinase inhibitors via design and synthesis of new alkylated indolyl-triazole Schiff bases for targeting breast cancer.

According to the World Health Organization (WHO) statistics: In 2020, there were 2.3 million women diagnosed with breast cancer and 685,000 deaths globally. Therefore, searching for new leads for fighting this type of cancer is necessary. VEGFR-2 kinase plays a crucial role in the proliferation, migration, and survival of breast cancer cells so, identifying novel inhibitors for VEGFR-2 could be effective in breast cancer treatment. Accordingly, novel heterocyclic compounds containing indole, 1,2,4-triazole, and glycosyl or allyl moieties were synthesized. The synthesized compounds were evaluated for their cytotoxic and apoptotic activities towards breast cancer cell lines (MCF7). In this regard, compounds 6, 17, and 18 exhibited promising cytotoxic activity against MCF-7 cells with IC50 values of 3.06, 1.18, and 3.02 µM compared to Sorafenib (IC50 = 2.13 µM). Interestingly, among the identified lead molecules, compound 17 displayed remarkable VEGFR2 inhibition activity with IC50 value of 19.8 nM compared to Sunitinib (IC50 = 75 nM) and Sorafenib (IC50 = 30 nM). Moreover, it is significantly stimulated apoptotic breast cancer cell death; it induced apoptosis by 17.4 %, arresting the cell cycle phases at G1 and S-phases. Additionally, in vivo (Xenograft model) study validated the anticancer activity of the hit compound 17, which showed a tumor inhibition ratio of 54.2 % compared to 5-FU (49.5%) with an improvement of hematological and biochemical parameters. The results disclosed that the identified hit compound 17 is validated for impeding cell proliferation and migration through apoptosis activation and VEGFR2 inhibition.

Synthesis of new substituted pyridine derivatives as potent anti-liver cancer agents through apoptosis induction: In vitro, in vivo, and in silico integrated approaches.

Liver cancer is the most common type of cancer in many countries. New studies and statistics show rising liver cancer worldwide, so it is essential to seek new agents for this type of cancer. PIM1 has an attractive target in the discovery of cancer medications as it is very much expressed in a variety of malignancies and influences such as tumorigenesis, cell cycle progression, cellular proliferation, apoptosis, and cell migration. Accordingly, a series of pyridones and pyridine-amides were synthesized and tested for anti-liver cancer activity. In the synthetic strategy 4,6-diaryl-3-cyano-2-pyridones 3a-n were synthesized using one-pot four component synthetic method. Structural modifications were done on 4,6-diphenyl-3-cayno-2-pyridone 3a to enhance the activity. Alkylation in the presence of K2CO3 afforded the O-alkylated products 4-6. The acetoxy hydrazide 7 was synthesized and cyclized into 1,3,4-oxadiazolethione 8 which alkylated on sulfur to give 10. Azide-coupling method was used to couple the 2-(pyridin-2-yloxy)acetohydrazide 7 to different amines and amino acid esters to furnish the products 12a-e and 13a-b. The synthesized derivatives were subjected to cytotoxic screening against HepG2 and THLE-2 cells, Compounds 10, 12e and 13a have a remarkable cytotoxic activity with IC50 values (10.7-13.9 µM). Compound 7 was found to be more cytotoxic by showing the lowest IC50 value of 7.26 compared to 5-FU (IC50 = 6.98 µM). It inhibited cell growth by 76.76%. Additionally, it significantly stimulated apoptotic liver cancer cell death with 49.78-fold (22.90% compared to 0.46% for the control) arresting cell cycle Pre-G1 with 35.16% of a cell population, compared to 1.57% for the control. Moreover, it validated the intrinsic apoptosis through upregulation of P53, and other related genes, with inhibition of anti-apoptotic genes through PIM-1 inhibition.

Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation.

A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 1. An interesting cyclization was obtained when the amino-ester 1 reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[2,3-d][1,3]thiazin-4-one 3. Acylation of the amino-ester 1 with chloroacetyl chloride in DCM and Et3N afforded the acylated ester 4. The amino-ester 1 was cyclized to benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one 8, which was reacted with some alkylating agents leading to alkylation at nitrogen 9-13. Hydrazide 14 was utilized as a synthon for the synthesis of the derivatives 15-19. Chloro-thieno[2,3-d]pyrimidine 20 was synthesized and reacted with the hydrazine hydrate to afford the hydrazino derivative 21, which was used as a scaffold for getting the derivatives 22-28. Nucleophilic substitution reactions were used for getting the compounds 29-35 from chloro-thieno[2,3-d]pyrimidine 20. In the way of anticancer therapeutics development, the requisite compounds were assessed for their cytotoxicity in vitro against MCF-7 and HepG-2 cancer cell lines. Twelve compounds showed an interesting antiproliferative potential with IC50 from 23.2 to 95.9 µM. The flow cytometric analysis results showed that hit 4 induces the apoptosis in MCF-7 cells with a significant 26.86% reduction in cell viability. The in vivo study revealed a significant decrease in the solid tumor mass (26.6%) upon treatment with compound 4. Moreover, in silico study as an agonist for inhibitors of JAK2 and prediction study determined their binding energies and predicted their physicochemical properties and drug-likeness scores.

Expeditious Green Synthesis of Novel 4-Methyl-1,2,5,6-tetraazafluoranthen-3(2H)-one Analogue from Ninhydrin: N/S-Alkylation and Aza-Michael Addition.

A straightforward green synthesis of 4-methyl-1,2,5,6-tetraazafluoranthen-3(2H)-one 6 is reported from ninhydrin 1 via condensation with ethyl acetoacetate, followed by cyclization with hydrazine hydrate in water as a benign solvent. Tetraazafluoranthen-3-thione 7 was obtained using Lawesson's reagent. N-alkylated tetraazafluoranthen-3-one 8-12 and S-alkylated analogues 13-15 were synthesized via alkylation. The investigation of the unique reactivity of 4-methyl-1,2,5,6-tetraazafluoranthen-3(2H)-one/thione toward the alkylation and aza-Michael additions was explored.

Synthesis of a New Series of Nitrogen/Sulfur Heterocycles by Linking Four Rings: Indole; 1,2,4-Triazole; Pyridazine; and Quinoxaline.

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2-6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7-16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7-13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19-25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.

Discovery of hydrazide-based pyridazino[4,5-b]indole scaffold as a new phosphoinositide 3-kinase (PI3K) inhibitor for breast cancer therapy.

Herein, the mono and dialkylation of pyridazino[4,5-b]indole were achieved with a set of alkylating agents, including amyl bromide, allyl bromide, benzyl bromide and ethyl chloroacetate in the presence of K2CO3/acetone or KOH/DMSO. The hydrazinolysis of mono and di-esters 10 and 11 gave the target hydrazides 12 and 13, which displayed promising, potent, and significant cytotoxic activity against the MCF-7 cell line with IC50 values of 4.25 and 5.35 µm compared to that of the standard drug 5-FU (IC50 6.98 µm), respectively. RT-PCR analysis of the most active compound 12 was performed to determine its mode of action through the up-regulation of pro-apoptotic genes and inhibition of anti-apoptotic and PI3K/AKT/mTOR genes. The findings were consistent with the proposed mechanism illustrated in the in silico study. Further, the in vivo analysis exhibited its potent anti-cancer activity through the prolongation of survival parameters, and inhibition of ascetic fluid parameters in EAC-bearing mice.

Synthesis and Anti-Proliferative Assessment of Triazolo-Thiadiazepine and Triazolo-Thiadiazine Scaffolds.

A series of triazolo-thiadiazepines 4a-k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b. The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a-k and not the enamine-tautomer 6a-k. The structures of the newly synthesized triazolo-thiadiazepines 4a-k and triazolo-thiadiazines 8a-b were elucidated using NMR (1H, and 13C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC50 between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the tested cancer cell lines respectively, compared to doxorubicin (IC50 4.0 µg/mL). Docking studies revealed that the thiadiazepine scaffold presented a suitable anchor, allowing good interaction of the various binding groups with the enzyme binding regions and sub-pockets.

Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation.

PARP-1, a nuclear protein, is one of the key member of the DNA repair assembly and thereby emerged as an attractive target in anti-cancer drug discovery. PARP-1 plays a key role in terms of base excision repair, which is an important pathway for cell survival in breast cancer with BRCA1/BRCA2-mutation. In this scenario, the goal of this study was to identify novel prototypes of PARP-1 inhibitors for the development of antitumor therapeutics to treat breast cancer. Thus, a structure-based drug design exploration was first conducted using an in-house library, focusing on triazole-thione and alkylsulfanyl-triazole scaffold. Hits with good binding affinity and better predicted inhibitory potential were also tested for their PARP-1 inhibitory activity. Moreover, the selected compounds were evaluated for their cytotoxicity in-vitro. This approach led to the identification of few novel compounds showing interesting anti-proliferative potential in low micromolar range. Results disclosed that the identified lead molecules were efficiently impeding cell migration and cell proliferation, potentially by interfering with PARP-1 enzymatic activities.

Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma.

Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity. The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC50 5.7 µg/mL and 7.09 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC50 values 7.25 µg/mL and 7.5 µg/mL, respectively compared to the standard compound cisplatin (IC50 9.0 µg/mL). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.

Design, selective alkylation and X-ray crystal structure determination of dihydro-indolyl-1,2,4-triazole-3-thione and its 3-benzylsulfanyl analogue as potent anticancer agents.

Three sets of substituted indolyl-triazoles were synthesized by the alkylation of 1,2-dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione with different alkyl halides. The use of pyridine restricted the alkylation to sulfur. Whereas, upon using K2CO3, the alkylation exceeded sulfur to one of the remaining triazole nitrogens. The assignment of which nitrogen is alkylated besides sulfur is made for the first time using X-ray analysis of single crystals and 2D NMR which indicated that S-, 2-N-isomers will be preferably formed over the S-, 1-N-isomers. The antiproliferative activity on HEPG-2 and MCF-7 cancer cell lines was tested. The results showed that compound 2a is the most active with an IC50 3.58 µg/mL and 4.53 µg/mL for HEPG-2 and MCF-7 respectively and compound 7 is the least active with an IC50 > 100 µg/mL compared to the standard drug doxorubicin (IC50 4.0 µg/mL). The interaction of the synthesized compounds with tyrosine kinases, namely, Akt, PI3, and EGFR was also studied using molecular docking simulation to predict their mode of action which will drive future work directions.

Choosing between the modified Ravitch and Nuss procedures for pectus excavatum: Considering the patients's perspective.

INTRODUCTION Pectus excavatum (PE) is the most common paediatric chest wall deformity. The majority of patients are treated for cosmetic purposes, with the modified Ravitch and Nuss procedures the most commonly performed. We tested the preferences of healthy individuals over their choice of procedure. METHODS The study was conducted from February to August 2014. A five-item illustrated questionnaire was administered to teenagers and young adults aged 14-26 years over their willingness to seek medical advice if they had PE, provided its cosmetic appearance was the only complaint. They were asked about their preference over the modified Ravitch and Nuss procedures, with the surgical details for both procedures explained by medical professionals, alongside illustrated outcomes. RESULTS Two hundred and two healthy individuals were interviewed. The median age was 19.5 years (14-26 years) and 141 (69.8%) were male. Sixty seven (33.2%) participants refused any intervention, while 11 (5.4%) initially wanted an intervention but refused after understanding the surgical procedures available. Of the 135 respondents who chose surgical correction, 84 (62.2%) preferred the modified Ravitch operation, while 51 (37.8%) preferred the Nuss procedure. The main reason for choosing the modified Ravitch technique was not having something metal in the chest, while most participants who chose the Nuss procedure felt that it was "cosmetically better". CONCLUSIONS Patients have preferences over the choice of procedure for PE repair that can affect the treatment decision. Paediatric and thoracic surgeons should therefore be experienced in performing both procedures.

Regioselectivity of the alkylation of S-substituted 1,2,4-triazoles with dihaloalkanes.

BACKGROUND: 1,2,4-Triazole3-thiones are good scaffolds for preparation of new lead compounds. Their derivatives attracted the attention of chemists due to their wide spectrum of biological activities. Alkylsulfanyl-1,2,4-triazoles have three nucleophilic sites (nitrogens) ready for reaction with electrophiles. Herein, new regioselective isomers were synthesized by the reaction of benzylsulfanyl-1,2,4-triazole with various dihaloalkanes. Regioselectivity was determined by X-ray crystallography and NMR. RESULTS: Coupling of 3-benzylsufanyl-5-(1H-indolyl)-1,2,4-triazole with dibromomethane, 1,2-dichloroethane, 1,3-dibromopropane and di(bromomethyl)quinoxaline was investigated in the presence of potassium carbonate in acetone. In the case of dibromomethane three different bis(triazolyl)methane isomers (-N (1)-CH2-N (1)-4, -N (1)-CH2-N (2)-5, -N (2)-CH2-N (2)-6) were formed in which the two bromide atoms were replaced by two triazole moieties. Among these isomers the reaction was regioselective towards the -N (1)-CH2-N (2)-5 isomer due to the steric effect. In the case of 1,3-dibromopropane two compounds were obtained due to the alkylation at N(2) to give 2-(3-bromopropyl)-triazole 8 and alkylation at N(1) was followed by cyclization at the indole nitrogen to form a condensed indolo-triazolo-diazepine 10. Upon alkylation of 3-benzylsufanyl-5-(1H-indolyl)-1,2,4-triazole with di(bromomethyl)quinoxaline, two bis(triazolyl-methyl)quinoxaline isomers were separated and characterized as (-N (1)-CH2-N (1)-) 11 and (-N (2)-CH2-N (2)-) 12. Single-crystal X-ray diffraction assisted the elucidation and confirmation of the structures of the isomers. An AM1 theoretical study explained the regioselectivity of the alkylation. CONCLUSIONS: On reacting S-protected 1,2,4-triazoles with various alkylating agents, only N(1) and N(2) attack the electrophilic carbons. N(2) alkylated isomers are preferentially formed. Graphical abstract.

Synthesis of New Functionalized Indoles Based on Ethyl Indol-2-carboxylate.

Successful alkylations of the nitrogen of ethyl indol-2-carboxylate were carried out using aq. KOH in acetone. The respective N-alkylated acids could be obtained without separating the N-alkylated esters by increasing the amount of KOH and water. The use of NaOMe in methanol led to transesterification instead of the alkylation, while the use of NaOEt led to low yields of the N-alkylated acids. Hydrazinolysis of the ester gave indol-2-carbohydrazide which then was allowed to react with different aromatic aldehydes and ketones in ethanol catalyzed by acetic acid. Indol-2-thiosemicarbazide was used in a heterocyclization reaction to form thiazoles. The new structures were confirmed using NMR, mass spectrometry and X-ray single crystal analysis.

Physico-chemical characteristics of oil produced from seeds of some date palm cultivars (Phoenix dactylifera L.) .

The oil content of saturated and unsaturated fatty acids with some physico-chemical properties and nutrients were investigated in oil produced from seeds of six important date palm cultivars and one seed strain present in Saudi Arabia. The results indicated that the oil extracted from six seed cultivars of date palm ranged from 6.73-10.89% w/w oil. The refractive index of date seeds oil was found to be between 1.4574 to 1.4615. The iodine values, acid values and saponification values were in the range of 74.2-86.6 g iodine 100 g(-1); 2.50-2.58 mg KOH g(-1) and 0.206-0.217 mg KOH g(-1), respectively. Lauric acid, Myristic acid, Palmitic acid C15, Palmitic acid C16 Stearic acid, Arachidic acid and Behenic acid of date seeds oil contents were found between 8.67-49.27; 7.01-15.43; 0-0.57; 4.82-18.09; 1.02-7.86; 0-0.08; and 0-0.15% w/w, in that order. Omega-6 and Omega-9 of date seeds oil were found between 7.31-17.87 and 52.12-58.78%, respectively. Khalas, Barhy cvs. and seed strain gave highest K and Ca, Na and Fe, Mg as compared with other studied cultivars.

First Report of Thielaviopsis punctulata Causing Black Scorch Disease on Date Palm in Qatar.

Ceratocystis radicicola (anamorph: Thielaviopsis paradoxa) was reported as an economically important pathogen causing serious diseases on date palm such as rhizosis (2) and black scorch (3) or as an associated pathogen with diseased date palm (1). In this study, we report for the first time that C. radicicola also causes black scorch disease in Qatar. In April to May 2013, we conducted a disease survey in 11 farms located in northern and southern Qatar where three infected farms had an average of 10% disease incidence. Infected trees manifested different disease symptoms such as black scorch of leaves, inflorescence blight, and heart and bud rot. Infected tissues were surface sterilized with 1.0% NaOCl for 60 s, rinsed with distilled water, blotted dry, and then plated on potato dextrose agar (PDA) supplemented with 50 mg/liter Rose Bengal. Single fungal colonies were picked from hyphal tips and grown on PDA for 7 days at 25°C for further examination of the mycological characteristics. Colonies of five C. radicicola isolates on PDA developed aerial mycelium with a light gray color in culture plate, which later changed to black. Both light and scanning electron microscopy were employed to delineate species by spore morphology. Colonies produced ovate aleuroconidia (14 to 17 × 9 to 12 µm) and cylindrical phialoconidia (7 to 9 × 3 to 4 µm) characteristic features of C. radicicola. Phialoconidia (endoconidia) were hyaline to brown in chains produced from endoconidiophore, clamydospores (aleuroconidia), which were single with smooth or slightly rough wall. Additionally, C. radicicola produced single alueroconidia from conidiophores. Amplification of ITS rDNA region from fungal genomic DNA of five isolates, using universal primers ITS1 (5'-TCCGTAGGTGAACCTGCGG-3') and ITS4 (5'-CCTCCGCTTATTGATATGC-3') confirmed the isolated fungus as C. radicicola with no intra-specific variation among the fungal isolates. The length of ITS-rDNA sequence was 534 bp (KJ410228) and had 99 and 93% sequence identity with ITS-rDNA region from C. radicicola (HQ443203) and C. paradoxa (HC415073.1), respectively. A pathogenicity test was conducted using 3-year-old trees from three cultivars (Khalas, Khneezi, and Barhi) growing in sandy loam soil under greenhouse conditions (25 to 29°C and 12/12-h light/dark). Six trees from each cultivar were used for pathogenicity test, where three were inoculated and three other mock-inoculated. Eight millimeter diameter mycelial plugs were obtained from a C. radicicola culture on PDA medium and used to inoculate rachis region and basal petioles of date palm leaves with a 9-mm wound created with a cork borer. Control plants were mock-inoculated with PDA plugs. The inoculated area was covered with wet cotton to prevent dryness and the whole plant was covered for 72 h. Four days post infection (dpi), a rusty black infection appeared on the plants. Fifteen dpi, the whole leaf of inoculated stem showed typical symptoms, from which the fungus was re-isolated and colonies were maintained in PDA for morphological characterization, which were confirmed as C. radicicola. All trees from three cultivars showed symptoms with a variable severity from cultivar to another. To our knowledge, this is the first report of black scorch disease caused by T. punctulata in Qatar. This report highlighted the incidence of black scorch disease in Qatar demanding future research study to control the pathogen. References: (1) Y. M. Al-Raisi et al. New Dis. Rep. 23:23, 2011. (2) C. Linde and W. A. Smit. Plant Dis. 83:880, 1999. (3) P. Suleman et al. Plant Dis. 85:80, 2001.

Regioselective synthesis, characterization and antimicrobial evaluation of S-glycosides and S,N-diglycosides of 1,2-Dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione.

Glycosylation of 1,2-Dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride was investigated in the presence of Et3N and K2CO3 as acid scavengers. A regioselective S-glycosides were obtained by using Et3N whereas, using K2CO3 gave a mixtures of two hybrids having two glycosidic bonds. The two products of each mixture were separated and characterized as S,N(1)- and S,N(2)-bis(glycosylated) derivatives. The structures of the newly synthesized compounds were elucidated by (1)H NMR, (13)C NMR, 2D NMR and mass spectra. The compounds were screened for their antibacterial and antifungal activities. Some compounds exhibited strong inhibition activity compared with the reference drugs (chloramphenicol and baneocin).