Search

Heshu Sulaiman Rahman,1,2 Hemn Hassan Othman,3 Nahidah Ibrahim Hammadi,4 Swee Keong Yeap,5 Kawa Mohammad Amin,6 Nozlena Abdul Samad,7 Noorjahan Banu Alitheen8 1Department of Physiology, College of Medicine, University of Sulaimani, Sulaymaniyah 46001, Republic of Iraq; 2Department of Medical Laboratory Sciences, College of Health Sciences, Komar University of Science and Technology, Sulaymaniyah, Republic of Iraq; 3Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaymaniyah 46001, Republic of Iraq; 4Department of Histology, College of Veterinary Medicine, University of Al-Anbar, Ramadi, Republic of Iraq; 5China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang, Malaysia; 6Department of Microbiology, College of Medicine, University of Sulaimani, Sulaymaniyah 46001, Republic of Iraq; 7Integrative Medicine Cluster, Institut Perubatan dan Pergigian Termaju (IPPT), Sains@BERTAM, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia; 8Department of Cell and Molecular Biology, Faculty of Biotechnology and Bio-Molecular Sciences, Universiti Putra Malaysia, Selangor, MalaysiaCorrespondence: Noorjahan Banu AlitheenDepartment of Cell and Molecular Biology, Faculty of Biotechnology and Bio-Molecular Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, MalaysiaTel +60 126866947Email noorjahan@upm.edu.myHeshu Sulaiman RahmanDepartment of Physiology, College of Medicine, University of Sulaimani, Sulaymaniyah 46001, Republic of IraqTel +964 7726159598Email heshu.rhaman@univsul.edu.iqAbstract: Many types of research have distinctly addressed the efficacy of natural plant metabolites used for human consumption both in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated for clinical use because of several factors such as inefficient systemic delivery and bioavailability of promising agents that significantly contribute to this disconnection. Over the past decades, extraordinary advances have been made successfully on the development of novel drug delivery systems for encapsulation of plant active metabolites including organic, inorganic and hybrid nanoparticles. The advanced formulas are confirmed to have extraordinary benefits over conventional and previously used systems in the manner of solubility, bioavailability, toxicity, pharmacological activity, stability, distribution, sustained delivery, and both physical and chemical degradation. The current review highlights the development of novel nanocarrier for plant active compounds, their method of preparation, type of active ingredients, and their biomedical applications.Keywords: nanomedicine, natural plant metabolite, biomedical application, carrier formulation, drug delivery

BACKGROUND: Myristica fragrans Houtt. (nutmeg) has been mentioned in Unani medicine to be of value in the management of male sexual disorders. The present study was undertaken to evaluate the aphrodisiac effect of 50% ethanolic extract of nutmeg along with its likely adverse effects and acute toxicity using various animal models. METHODS: The suspension of the extract was administered (100, 250 and 500 mg/kg, p.o.) to different groups of male rats daily for seven days. The female rats involved in mating were made receptive by hormonal treatment. The general mating behaviour, libido and potency were studied and compared with the standard reference drug sildenafil citrate. Likely adverse effects and acute toxicity of the extract were also evaluated. RESULTS: Oral administration of the extract at the dose of 500 mg/kg, produced significant augmentation of sexual activity in male rats. It significantly increased the Mounting Frequency, Intromission Frequency, Intromission Latency and caused significant reduction in the Mounting Latency and Post Ejaculatory Interval. It also significantly increased Mounting Frequency with penile anaesthetization as well as Erections, Quick Flips, Long Flips and the aggregate of penile reflexes with penile stimulation. The extract was also observed to be devoid of any adverse effects and acute toxicity. CONCLUSION: The resultant significant and sustained increase in the sexual activity of normal male rats without any conspicuous adverse effects indicates that the 50% ethanolic extract of nutmeg possesses aphrodisiac activity, increasing both libido and potency, which might be attributed to its nervous stimulating property. The present study thus provides a scientific rationale for the traditional use of nutmeg in the management of male sexual disorders. [ABSTRACT FROM AUTHOR]

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC 50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC 50  = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Understanding healthcare-seeking behavior and examining health expenditures can help determine possible barriers to accessing healthcare and direct more effective and inclusive healthcare systems. This study aimed to evaluate healthcare-seeking behavior and out-of-pocket healthcare expenditure in a sample of the population in Erbil, Iraq., Methods: We conducted this cross-sectional study in Erbil, Kurdistan Region of Iraq, from October to December 2023. A convenience sample of 414 adults completed a self-administered online survey. The following data were collected: recent illness, sociodemographic characteristics, type of healthcare received, and cost of healthcare., Results: The most common health conditions reported were communicable diseases (16.3%), musculoskeletal problems (13.1%), and noncommunicable diseases (12.7%). Approximately 85% of patients with health conditions requiring care sought healthcare; most visited private clinics (46.3%) and private hospitals (18.6%). The median total out-of-pocket healthcare expenditure in US dollars was 117.3 (interquartile range (IQR) = 45.6-410.0). The median total cost was much greater for participants who first visited a private health facility (USD 135.5, IQR = 57.3-405.6) than those who first visited a public facility (USD 76.8, IQR = 16.1-459.7). Participants ≥ 60 years spent significantly more than those < 14 years (USD 332, 95% CI = 211-453, p < 0.001). Evermarried participants spent significantly more than unmarried (USD 97, 95% CI = 1 to 192, p = 0.047). Health expenditures were significantly greater for noncommunicable diseases than infectious diseases (USD 232, 95% CI = 96-368, p = 0.001). After adjusting for covariates, age ≥ 60 years was independently associated with higher spending (USD 305, 95% CI = 153-457, p < 0.001)., Conclusions: Most participants sought care from formal health services, preferring the private sector. Seeking care from private facilities incurred significantly higher costs than seeking care from public ones, which suggests potential barriers to accessing healthcare, particularly affordability. The findings underscore the importance of evaluating existing healthcare policies to enhance effectiveness and identify areas for improvement. This study can help policymakers and healthcare providers design effective interventions, allocate resources efficiently, and improve healthcare delivery., (© 2024. The Author(s).)

The present study investigated the relationship between single nucleotide polymorphisms in the interleukin (IL)-15 gene located (exon 8) on the chromosomal location 4q31.21 and acute lymphoblastic leukaemia (ALL) risk in Iraqi patients. A total of 78 (49 male -29 female) primary ALL (62B-cell, 16 T-cells lineages cases and 30 healthy control subjects (median age 11, age range were 4-21.5), were enrolled at the Nanakaly Hospital of Erbil Province between February 2021 and January 2022. The genotype analysis was performed using polymerase chain reaction (PCR) and Sanger DNA sequencing. The IL15 homozygous rs10833 (100%) and rs2291596 (63.6%) genotypes indicated high frequencies and were associated with a risk of developing ALL, while the remaining 16 novel mutations indicated in low frequency (9.1%) except for the 97270G>GT genotype (18.2%). High expression levels were noted for different clusters of differentiation (CD) biomarkers between both subtypes of ALL, including, CD10, CD19, CD22, CD79a, CD99,  terminal deoxynucleotidyl transferase (TdT), and human leukocyte antigen DR (HLA-DR) isotype in B-cells lineages, while, CD2, CD3, CD5, CD7, CD13, CD117 and TdT are more specific to T-cells lineages. On the other hand,  significant changes were noted in certain hematological parameters including red blood cells (RBCs), haemoglobin (g/dl), haematocrite (HCt %), red blood cell distribution width (RDW %), and platelet counts (PLT- 109/L) compared with those of healthy subjects. Finally, it was concluded that various novel mutations were recorded with different subtypes of ALL diseases, and mild anemia was observed among patients. Future studies will be towered to associate these mutations with prognosis and therapeutic response of diseases.

New series of thiazolyl-pyrazoline derivatives ( 7a-7d , 10a-10d and 13a-13f ) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC 50 = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC 50 = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC 50 = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC 50 = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed a novel series of 34 pyridopyrazinone derivatives as anticancer agents (series A - H ). Herein, a multi-step in silico approach was preliminary conducted to evaluate the predicted PDE5 inhibitory activity, followed by an in vitro biological evaluation over the enzymatic level and a detailed SAR study. The designed 2D-QSAR model which was carried out to predict the IC 50 of the tested compounds revealed series B , D , E and G with nanomolar range of IC 50 values (6.00-81.56 nM). A further docking simulation model was performed to investigate the binding modes within the active site of PDE5. Interestingly, most of the tested compounds showed almost the same binding modes of that of reported PDE5 inhibitors. To validate the in silico results, an in vitro enzymatic assay over PDE5 enzyme was performed for a number of the promising candidates with different substitutions. Both series E and G exhibited a potent inhibitory activity (IC 50 = 18.13-41.41 nM). Compound 11b (series G , oxadiazole-based derivatives with terminal 4-NO 2 substituted phenyl ring and rigid linker) was the most potent analogue with IC 50 value of 18.13 nM. Structure-activity relationship (SAR) data attained for various substitutions were rationalized. Furthermore, a molecular dynamic simulation gave insights into the inhibitory activity of the most active compound ( 11b ). Accordingly, this report presents a successful scaffold repurposing approach that reveals compound 11b as a highly potent nanomolar PDE5 inhibitor worthy of further investigation.

Breast cancer is the most common malignancy worldwide; therefore, the development of new anticancer agents is essential for improved tumor control. By adopting the pharmacophore hybridization approach, two series of 7-hydroxyl-4-methylcoumarin hybridized with thiosemicarbazone ( V-VI ) and thiazolidin-4-one moieties ( VII-VIII ) were prepared. The in vitro anticancer activity was assessed against MCF-7 cells adopting the MTT assay. Nine compounds showed significant cytotoxicity. The most promising compound, VIIb , induced remarkable cytotoxicity (IC 50 of 1.03 + 0.05 µM). Further investigations were conducted to explore its pro-apoptotic activity demonstrating S-phase cell cycle arrest. Apoptosis rates following VIIb treatment revealed a 5-fold and 100-fold increase in early and late apoptotic cells, correspondingly. Moreover, our results showed caspase-9 dependent apoptosis induction as manifested by an 8-fold increase in caspase-9 level following VIIb treatment. Mechanistically, VIIb was found to target the PI3K-α/Akt-1 axis, as evidenced by enzyme inhibition assay results reporting significant inhibition of examined enzymes. These findings were confirmed by Western blot results indicating the ability of VIIb to repress levels of Cyclin D1, p-PI3K, and p-Akt. Furthermore, docking studies showed that VIIb has a binding affinity with the PI3K binding site higher than the original ligands X6K. Our results suggest that VIIb has pharmacological potential as a promising anti-cancer compound by the inhibition of the PI3K/Akt axis.

Breast cancer is the most prevalent malignant neoplasm in females. Genetic variations in the xenobiotic metabolising cytochrome enzymes; Family 1 Subfamily A Member 1 (CYP1A1) and Family 1 Subfamily B Member 1 (CYP1B1) might play a role in the individual susceptibility to breast cancer and its prognosis. The goal of this study is to estimate the incidence of single nucleotide polymorphisms (SNPs) in CYP1A1 (rs1048943, Ile462VaI, and rs4646903/MSP1) and in CYP1B1 (rs1056836, Leu432Val) genes in patients with breast cancer. This case-control study included 180 female patients with breast cancer and 180 healthy control subjects from Kirkuk/Iraq. Genomic DNA was extracted from venous blood samples and tested for SNPs by the direct DNA sequencing technique. A statistical analysis was done to identify if there is any association between SNPs and the increasing odd of breast cancer and its stage, grade and molecular subtype at diagnosis. The common (reference) genotype of CYP1A1 gene rs1048943 is AA. The AG and GG variant genotypes were significantly more common in the breast cancer patients and conferred an increased odd of breast cancer and its later stages (stages III and IV) and poor differentiation ( P  < .01) but not with the molecular subtypes. The common genotype of CYP1A1 rs4646903 is TT. The variant genotypes TC and CC are not associated either with increased risk of breast cancer ( P  > .05) or with its stage, grade or molecular subtypes ( P  > .05). The GG genotype of CYP1B1 rs1056836 was the common genotype. The CG and CC variant genotypes were not associated with the increased risks of breast cancer ( P  > .05) or its stage, grade or molecular subtypes ( P  > .05). In conclusion, variants genotypes of CYP1A1 rs1048943 might play a role in breast cancer pathogenesis and prognosis and can have a place in cancer screening and tailored medicine in the future in the Iraqi population. Future larger scale studies including other genes might help to better understand the role of the SNP in breast risk and its prognosis., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Some 3-phenyl-quinazolin-4(3H)-one-2-thioethers (3a-e, 5a,b, 7a-e, 9a-d, 10a-d, and 12) along with 2-aminoquinazoline derivatives 13a-c were prepared and screened for their in vitro phosphodiesterase (PDE) inhibitory activity. Some compounds such as 7d,e, 9a,b,d, 10a,d, and 13b exhibited promising activity as compared with the non-selective PDE inhibitor IBMX. This inhibitory activity was validated by molecular docking in the active site of PDE7A and PDE4 to investigate their selectivity. Furthermore, the most active compound 10d (IC 50  = 1.15 μM) was tested in vivo using behavioral tests. Compound 10d was able to pass the blood-brain barrier and improve scopolamine-induced cognitive deficits. Therefore, this core can be considered as a promising scaffold for further optimization to obtain new compounds with better PDE7A selective inhibition., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Nickel cobalt layered double hydroxide (NiCo-LDH)-based materials have recently emerged as catalysts for important electrochemical applications. However, they frequently suffer from low electrical conductivity and agglomeration, which in turn impairs their performance. Herein, we present a catalyst design based on integrated, self-supported nickel nanotube networks (Ni-NTNWs) loaded with NiCo-LDH nanosheets, which represents a binder-free, hierarchically nanostructured electrode architecture combining continuous conduction paths and openly accessible macropores of low tortuosity with an ultrahigh density of active sites. Similar to macroscale metallic foams, the NTNWs serve as three-dimensionally interconnected, robust frameworks for the deposition of active material, but are structured in the submicron range. Our synthesis is solely based on scalable approaches, namely templating with commercial track-etched membranes, electroless plating, and electrodeposition. Morphological and compositional characterization proved the successful decoration of the inner and outer nanotube surfaces with a conformal NiCo-LDH layer. Ni-NTNW electrodes and hydroxide-decorated variants showed excellent performance in glucose sensing. The highest activity was achieved for the catalyst augmented with NiCo-LDH nanosheets, which surpassed the modification with pure Ni(OH) 2 . Despite its low thickness of 20 µm, the optimized catalyst layer provided an outstanding sensitivity of 4.6 mA mM -1 cm -2 , a low detection limit of 0.2 µM, a fast response time of 5.3 s, high selectivity and stability, and two linear ranges covering four orders of magnitude, up to 2.5 mM analyte. As such, derivatized interconnected metal nano-networks represent a promising design paradigm for highly miniaturized yet effective catalyst electrodes and electrochemical sensors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Twenty novel 7-benzyloxycoumarin based compounds were synthesized with a variety of bioactive chemical fragments. The synthesized compounds showed remarkable acetylcholinesterase (AChE) inhibitory activity. In vitro assay revealed that compounds 7-benzyloxy-4-{[(4-phenylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H-chromen-2-one (5b, IC 50 = 0.451μM), 7-benzyloxy-4-({[4-(4-methoxyphenyl)thiazol-2(3H)-ylidene]hydrazono}methyl)-2H-chromen-2-one (5d, IC 50 = 0.625μM), 5-amino-1-[2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-1H-pyrazole-4-carbonitrile (13c, IC 50 = 0.466μM), 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2-methylimino-4-phenylthiazol-3(2H)-yl)acetamide (16a, IC 50 = 0.500μM) and 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-[4-(4-methoxyphenyl)-2-methyliminothiazol-3(2H)-yl]acetamide (16b, IC 50 = 0.590μM) exhibited promising AChE inhibitory activity even better than donepezil (IC 50 = 0.711μM). Kinetic study for compound 5b implied mixed type inhibitor which could bind peripheral anionic site (PAS) and catalytic active site (CAS) of AChE enzyme. In addition, in vivo evaluation of compounds 5b, 13c and 16a confirmed significant memory improvement in scopolamine-induced impairment model in tested mice. Furthermore, in silico studies were performed on the synthesized compounds which included molecular docking study at the active site of recombinant human acetylcholinesterase enzyme (rhAChE) as well as prediction of ADMET and other physicochemical parameters. A correlation between the docking results and IC 50 of tested compounds was routinely observed and shared similar binding pattern to the co-crystallized ligand donepezil., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Foot-and-mouth disease (FMD) is endemic in Iraq. The current study can be considered as the first molecular characterization of serotype O in Iraq. The present investigation reported the determination of FMDV serotype O from local farms in Sulaimani districts in 2016 outbreaks. Samples were collected from suspected cattle. The virus was primarily detected with RT-PCR directly from mouth epithelial samples. The direct sequencing and subsequent analysis of amplified PCR products for the VP1 gene indicated the circulation of serotype O of FMD in studied areas. Moreover, phylogenetic analysis revealed that the field isolated serotype O belonged to topotype ME-SA and lineage PanAsia II and clustered with Pakistan and Iran isolates (KU365843 and KY091283) with identity (96.00%, 95.00%) respectively. Furthermore, according to the phylogenic tree, the field isolates had different lineage with the three O/Manisa vaccine strains and Iraq/2000 strains. These findings highlighted the continuous circulation of serotype O of FMD in the region., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 Urmia University. All rights reserved.)

Ethnopharmacological Relevance: In recent years, oxidative stress (OS) and the generation of ROS have been recognized as a fundamental pathology contributing, at least partially, to a number of important diseases. However, the therapeutic application has been simplistically limited to using antioxidants with little correction of diseases, and many biomarkers of OS, although confirming and quantifying the magnitude of this pathology, are not suggestive of the underlying causes behind generation of a large amount of free radicals. Unfortunately, research has not noted the multi-implication parallel phenomenon of Ihtiraq (Combustion) in Unani Medicine, which possesses much richer etiopathological sub-typing and much more variegated selective and specific treatments (and prophylactics) corresponding to each sub-type of Ihtiraq; the identification of each sub-type's molecular counterparts can be used to develop not only sub-types of OS pathologies and corresponding selective treatments/prophylactics but also non-biomolecular factors. Eminent Unani physicians described a deteriorative phenomenon, which they termed as 'Ihtiraq' which stands for extreme metabolism or 'combustion' and is recognized as a fundamental pathology, contributing as a major factor to the development of chronic diseases. Further, Unani Medicine also possesses a pathophysiological phenomenon called 'Hararat Ghariba' (Unnatural Heat) whose diverse associations with Ihtiraq may be correlatable as upstream, parallel, or downstream associations of OS and consequent pathologies., Aim of the Study: The aim of the study is to: 1. Explore the correlation of the phenomenon and etiopathology of Ihtiraq and OS and the treatment and prevention of the pathologies arising from them. 2. Extrapolate Ihtiraq, its types, causes, prevention, and treatment to OS, hitherto existing as a fundamental and monolithic pathology of increased ROS, to hypothesize its molecular-level sub-typing, as well as to propose selective interventions in these molecular sub-types of OS in place of the existing use of only basic antioxidants such as Vitamin C., Material and Methods: This review is presented with a noteworthy insight into Unani concepts and a thorough study of classical Unani literature by Ibn Sina (10th century), Zakaria Razi (9th century), Ibn Rushd (12th century), Ibn al-Nafees (13th century), Majusi (10th century), and Jurjani (11th century), and comparative detailed study of modern concepts of OS from literature databases, as well as Google, recent researches, and review articles., Result: The study showed very close correspondences between the phenomenon, etiopathology, and treatment and prevention of Ihtiraq in Unani Medicine and OS in contemporary biomolecular medicine. It also revealed sub-types of Ihtiraq and corresponding selective Unani treatments and prophylactics including drugs and non-drug factors., Conclusion: After a comprehensive study and analysis of the most recent researches and classical theories, it can be stated that OS can be seen as a molecular level expression of Ihtiraq. Further, various components of Ihtiraq may be used to hypothesize molecular sub-types of OS and propose corresponding specific interventions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Twenty four 6-aminocoumarin based derivatives were synthesized according to two schemes. All the compounds were screened for their acetylcholinesterase inhibitory activity where compound 5b proved to be the most potent AChE inhibitor with (IC 50  = 37 nM) compared to tacrine and donepezil (IC 50  = 55.0 and 59.0 nM, respectively). Six compounds 2f, 2g, 4b, 5b, 8b and 9b revealed superior activity over donepezil and a conclusive structure activity relationship study was conducted explaining the obtained results. Furthermore, compounds 2f, 4b and 5b were investigated for their neurobehavioral effect in vivo. All the tested compounds showed improvement of neurobehavioral experiments using donepezil as reference drug. In addition, compounds 2f, 4b and 5b were able to reduce extracellular deposition of amyloid beta 42 in a comparable manner to donepezil. The binding modes of the synthesized compounds were evaluated in silico via molecular docking in the active site of AChE, as well as molecular dynamics simulation study. A pharmacophore model was generated for the newly synthesized compounds., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC 50 values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC 50 values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC 50 value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC 50  = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC 50  = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of new visnagin and benzofuran scaffold-based molecules was designed and synthesized as anti-inflammatory and analgesic agents. Biological screening of these compounds showed that they exhibit potent anti-inflammatory/analgesic activity with a safer side effect profile in in vivo mouse models. In vitro cyclooxygenase (COX) inhibition assay showed that the compounds elicit their function through selective COX-2 inhibition. Molecular docking study also revealed the ability of the compounds to correctly recognize the active site and achieve noncovalent binding interactions with key residues therein. The best combined profile of anti-inflammatory, analgesic and COX-2 selective inhibition properties in association with low gastrotoxicity was displayed by the analogs 8, 11b and 19d, which can be considered as promising leads for further future optimization.

Background and Objectives: White blood cells (WBCs) differential counting yields valued information about human health and disease. The current developed automated cell morphology equipments perform differential count which is based on blood smear image analysis. Previous identification systems for WBCs consist of successive dependent stages; pre-processing, segmentation, feature extraction, feature selection, and classification. There is a real need to employ deep learning methodologies so that the performance of previous WBCs identification systems can be increased. Classifying small limited datasets through deep learning systems is a major challenge and should be investigated., Methods: In this paper, we propose a novel identification system for WBCs based on deep convolutional neural networks. Two methodologies based on transfer learning are followed: transfer learning based on deep activation features and fine-tuning of existed deep networks. Deep acrivation featues are extracted from several pre-trained networks and employed in a traditional identification system. Moreover, a novel end-to-end convolutional deep architecture called "WBCsNet" is proposed and built from scratch. Finally, a limited balanced WBCs dataset classification is performed through the WBCsNet as a pre-trained network., Results: During our experiments, three different public WBCs datasets (2551 images) have been used which contain 5 healthy WBCs types. The overall system accuracy achieved by the proposed WBCsNet is (96.1%) which is more than different transfer learning approaches or even the previous traditional identification system. We also present features visualization for the WBCsNet activation which reflects higher response than the pre-trained activated one., Conclusion: a novel WBCs identification system based on deep learning theory is proposed and a high performance WBCsNet can be employed as a pre-trained network., (Copyright © 2017. Published by Elsevier B.V.)

A series of 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides IXa-l and their acetate esters Xa-l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) tests in mice. Further, neurotoxicity, hepatotoxicity, and acute toxicity were determined. All the new candidates displayed 100% anticonvulsant activity in the scPTZ screen in the dose range of 0.0057-0.283 mmol/kg. The most potent compounds in the scPTZ screen were Xh (ED 50  = 0.0012 mmol/kg), Xd (ED 50  = 0.002 mmol/kg), Xf (ED 50  = 0.004 mmol/kg), IXj (ED 50  = 0.0047 mmol/kg), Xl (ED 50  = 0.0076 mmol/kg), and Xi (ED 50  = 0.008 mmol/kg). They exhibited higher fold activity in the anticonvulsant potential than the gold standards, phenobarbital and ethosuximide. Compound Xf was active in both scPTZ and MES screens. It showed ED 50 of 0.016 mmol/kg in MES screen. In the neurotoxicity screens, none of the test compounds displayed any minimal motor impairment at the maximum administered dose. The 3D pharmacophore model using Biova 1 Discovery Studio 2016 programs exhibited high fit value. The anticonvulsant evaluation results were compatible with the molecular modeling study., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

Aim: Computer-aided drug design techniques were adopted to design three series of 2-substituted-5-nitrobenzimidazole derivatives hybridized with piperzine 5a,b, oxadiazole 7a,b, 9, 14a-c and triazolo-thiadiazole moieties 12a-d, as VEGFR-2/c-Met kinase inhibitors., Materials & Methods: The designed compounds were synthesized adopting the chemical pathways outlined in schemes 1 and 2 to afford the desired three series followed by evaluating their inhibitory activities against VEGFR-2 and c-Met and in vitro anticancer activities., Result: Analogs bearing substituted phenyl ring attached to oxadiazole ring 14a showed the greatest inhibitory activities against non-small-cell lung cancer NCI-H522 and melanoma SK-MEL-2 with inhibition percent of 48.70 and 42.62, respectively. Moreover, unsubstituted phenoxymethyl derivative 12d exhibited promising inhibitory activity against VEGFR-2 and c-Met (35.88 and 88.48%), respectively., Conclusion: The above results revealed that 2-substituted-5-nitrobenzimidazole hybridized with various heterocyclic scaffolds could be a potential anticancer agent.

This study deals with synthesis of a new set of benzofuran and 5H-furo[3,2-g]chromone linked various heterocyclic functionalities using concise synthetic approaches aiming to gain new antiproliferative candidates against MCF-7 breast cancer cells of p38α MAP kinase inhibiting activity. The biological data proved the significant sensitivity of breast cancer cell lines MCF-7 towards most of the prepared compounds in comparison with doxorubicin. In addition, compounds IIa,b, Va,b, VIa,b, VIIa,b, VIIIa,b, XIc showed significant in vitro p38α MAPK inhibiting potency comparable to the reference standard SB203580. Cell cycle analysis and apoptosis detection data demonstrated that compound VIa induced G2/M phase arrest and apoptosis in MCF-7 cancer cells, in addition to its activation of the caspases-9 and -3. Gold molecular docking studies rationalized the highly acceptable correlation between the calculated docking scores of fitness and the biological data of p38α MAP kinase inhibition. The newly prepared benzofuran and 5H-furo[3,2-g]chromone derivatives might be considered as new promising nuclei in anti-breast cancer chemotherapeutics for further functionalization, optimization and in-depth biological studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Enantioseparation of substituted 1,3-diazaspiro[4.5]decan-4-ones (1-14) was achieved using different polysaccharide type chiral stationary phases (CSPs), namely, Chiralcel OJ, Chiralcel OD and Lux-Amylose-2 using different mobile phases which were either n-hexane/2-propanol or n-hexane/ethanol mixtures of various ratios (v/v) at flow rate 1 mL min-1. UV detection was carried out at 254 nm and temperature of 20°C. The retention behavior and selectivity of these CSPs were examined in isocratic normal phase high-performance liquid chromatography mode. The results revealed that the amylose CSP (Lux-Amylose-2) could separate almost all the compounds under investigation in contrast to cellulose CSPs (Chiracel OJ and Chiracel OD) which resolved fewer compounds., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A novel series of coumarin-thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1 H NMR, 13 C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60-cell line panel according to the US NCI-DTP protocol or a selection of human tumor cell lines: breast cancer (MCF-7), liver cancer (HepG-2), and colorectal cancer (HCT-116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with K SV  = 4.27 × 10 5  M -1 . Moreover, the results for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with K SV 4.27 × 10 5 , 3.96 × 10 5 , and 3.51 × 10 5  M -1 , respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60-cell line panel, the leukemia HL-60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61% growth, followed by the lung carcinoma cell line NCI-H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC 50 value of 24.9 μg/mL against the HepG-2 cell line., (© 2017 Deutsche Pharmazeutische Gesellschaft.)

Background: White blood cells (WBCs) play a crucial role in the diagnosis of many diseases according to their numbers or morphology. The recent digital pathology equipments investigate and analyze the blood smear images automatically. The previous automated segmentation algorithms worked on healthy and non-healthy WBCs separately. Also, such algorithms had employed certain color components which leak adaptively with different datasets., Methods: In this paper, a novel segmentation algorithm for WBCs in the blood smear images is proposed using multi-scale similarity measure based on the neutrosophic domain. We employ neutrosophic similarity score to measure the similarity between different color components of the blood smear image. Since we utilize different color components from different color spaces, we modify the neutrosphic score algorithm to be adaptive. Two different segmentation frameworks are proposed: one for the segmentation of nucleus, and the other for the cytoplasm of WBCs. Moreover, our proposed algorithm is applied to both healthy and non-healthy WBCs. in some cases, the single blood smear image gather between healthy and non-healthy WBCs which is considered in our proposed algorithm. Also, our segmentation algorithm is performed without any external morphological binary enhancement methods which may effect on the original shape of the WBC., Results: Different public datasets with different resolutions were used in our experiments. We evaluate the system performance based on both qualitative and quantitative measurements. The quantitative results indicates high precision rates of the segmentation performance measurement A1 = 96.5% and A2 = 97.2% of the proposed method. The average segmentation performance results for different WBCs types reach to 97.6%., Conclusion: In this paper, a method based on adaptive neutrosphic sets similarity score is proposed in order to detect WBCs from a blood smear microscopic image and segment its components (nucleus and the cytoplasm). The proposed segmentation algorithm can be utilized for fully-automated classification systems, such systems can be either for the healthy WBCs or even for non-healthy WBCs specially the leukemia cells.

Based on the reported high expression of p38α MAP kinase in invasive breast cancers and the activity of different functionalized chromone derivatives as p38α inhibitors, a new set of 4,9-dimethoxy/4-methoxy-7-methyl-5-oxo-5H-furo[3,2-g]chromone derivatives were efficiently synthesized aiming to introduce new p38α MAP kinase suppressors as new anti-breast cancer tools. Using GOLD program, molecular docking study of the target compounds into p38α MAP kinase binding pocket was performed to highlight their scores, mode of binding and the important interactions to the amino acid residues of the enzyme. MTT assay investigated that fifteen target compounds produced marked cytotoxic potency higher than that obtained by Doxorubicin against MCF-7 cancer cells of IC 50 values ranging from 0.007 to 0.17μM vs IC 50 ; 0.62μM of doxorubicin. Eleven selected compounds were evaluated for their inhibitory potency against p38α MAPK kinase. The derivatives IVa, Va,b, VIa, IXb and XIIIa represented significant activity (IC 50 ; 0.19-0.67μM) comparing to the reference drug SB203580 (IC 50 ; 0.50μM). In virtue of its promising cytotoxic and p38α MAP kinase inhibition potency, the furochromone derivative IXb was selected as a representative example to investigate its mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cell lines. The results showed that the compound IXb induced cell cycle cessation at G2/M phase preventing its mitotic cycle, alongside its noteworthy activation of caspases-9 and -3 which might mediate the apoptosis of MCF-7 cells., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A series of novel spiroimidazolidinone derivatives 6a-d and 8a-x were synthesized and biologically evaluated for their anticonvulsant activity in the maximal electroshock seizure (MES) assay and the subcutaneous pentylenetetrazole (scPTZ) screening test. Compound 8w was the most active derivative in the scPTZ screening test with an ED50 value by about 5- and 83.6-fold lower than those of phenobarbital and ethosuximide as reference drugs, respectively. Most of the tested compounds exhibited moderate to weak activity in the MES screen test, except for 8a which displayed 100% protection at 0.09 mmol/kg. Moreover, all the test compounds did not show any minimal motor impairment in the neurotoxicity test., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

HER1 and HER2 are frequently overexpressed in human tumors where they drive cellular proliferation. For this reason they are considered important targets in anticancer therapy with dual HER1/HER2 inhibitors being recently approved and marketed. In this paper we report the identification of a series of compounds with anticancer activity by a combined virtual screening approach on the kinase domains of HER1 and HER2. 6 hit compounds that present a sub- or low-micromolar activity in two cell-based assays, were initially identified and a subsequent design cycle led to the synthesis of a compound with nanomolar activity in the cell-based assays., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Based on the reported anticancer activity of coumarin and pyrazoline derivatives, the present investigation dealt with the design and synthesis of coumarin derivatives bearing diversely substituted pyrazoline moieties 7-10. The non-cyclic isosteres 11a-e of compounds 10a-e were synthesized for comparative reasons. The target compounds were synthesized from 8-acetyl-7-methoxycoumarin that underwent Claisen-Schmidt condensation with various aldehydes to give the chalcones 6a-e, followed by reaction with hydrazine hydrate, phenyl hydrazine or semicarbazide under the appropriate conditions. Cytotoxicity of the synthesized compounds was evaluated in vitro against liver HepG2 cell line. Compounds were active in the nanomolar range. The most active compounds were investigated for their telomerase inhibition and proapoptotic activities., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

West Nile virus (WNV) is a human pathogen which is rapidly expanding worldwide. It is a member of the Flavivirus genus and it is transmitted by mosquitos between its avian hosts and occasionally in mammalian hosts. In humans the infection is often asymptomatic, however, the most severe cases result in encephalitis or meningitis. Approximately 10% of cases of neuroinvasive disease are fatal. To date there is no effective human vaccine or effective antiviral therapy available to treat WNV infections. For this reason, research in this field is rapidly growing. In this article we will review the latest efforts in the design and development of novel WNV inhibitors from a medicinal chemistry point of view, highlighting challenges and opportunities for the researchers working in this field.

Despite recent progress in antithrombotic therapy, there's still an unmet medical need for safe and orally available anticoagulants. Encouraged by the marked antithrombotic and anticoagulant activities of some coumarin derivatives, twenty-three new N-coumarinyl-4-amidinobenzamides 4a-f and 6-heterocycle substituted coumarin derivatives 5, 6a,b, 10a-e, 12a-e and 14a-d were synthesized and evaluated for their in vivo antithrombotic activity. The most active congeners were the unsubstituted amidine 4a (36.5 s), coumarinyl oxadiazole 5 (42.3 s), bis coumarinyl oxadiazole 6b (37.8 s) and coumarinyl pyrazole 10b (38.5 s) that presented prothrombin time (PT) values comparable to the reference drug warfarin (42.3 s). Furthermore, docking studies were undertaken to gain insight into the possible binding mode of these compounds with the coagulation factor Xa (FXa) binding site., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Novel series of spiro[(2H,3H)-quinazoline-2,1'-cyclohexane] derivatives (I-XVI) were synthesized and biologically evaluated as cytotoxic agents against human breast carcinoma cell lines (MCF-7) using doxorubicin as a reference drug. Most of the tested compounds displayed promising cytotoxic activity, especially derivatives V, VIb and XIb. The most active compounds were docked into the PARP-1 enzyme binding site to predict the ligand-protein binding modes. Lipinski rule of five and ADME profile suggested strongly that compounds V and VIb are promising agents as breast cancer inhibitors with drug likeness approach that have PARP-1 inhibitory activity. The structures of all newly synthesized compounds were confirmed by microanalysis and IR, 1H-NMR and mass spectral data.

Molecular docking simulation study was carried out to design a novel series of spiro [(2H, 3H)quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives as a new class of effective PARP-1 inhibitors. Spiro [2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H)-one (5) was the starting compound to synthesize the target proposed analogues. The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti-proliferative activity against the cultured human breast carcinoma cell line (MCF-7) using doxorubicin as a standard drug. Additionally, the compounds that exhibited the highest cytotoxic efficiency were further subjected to PARP-1 enzyme assay taking 3-aminobenzamide as the reference drug. The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data.

Two groups of coumarin-pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,β-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC(50) ranging from 0.01 μM to 2.8 μM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α)., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

New series of bioactive 7-oxycoumarin derivatives were synthesized and tested for their in vitro and in vivo monoamine oxidase (MAO) A and B inhibitory effect. In vitro studies revealed exceptionally potent and selective MAO-A inhibitors with K(i) values on a picomolar range. The acetohydrazide (3b) and the dioxopyrrolidine derivative (7b) showed the most potent in vitro and in vivo MAO inhibition activity. Moreover, molecular modeling study of the synthesized compounds into MAO-A (PDB: 2Z5X) and MAO-B (PDB: 2XFN) binding sites exhibited direct correlation between AutoDock binding affinity and% inhibition MAO-A (pM) and MAO-B (μM). In addition, the results of in vivo MAO inhibiting properties (ED(50)) of the tested compounds revealed better direct correlation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

New series of 4-methyl and 3,4-dimethyl-7-oxycoumarin derivatives (oxadiazoles, thiadiazoles, triazoles, and thiazolidinones) were designed, synthesized, and evaluated for their monoamine oxidase (MAO) A and B inhibiting effect. All the synthesized compounds showed in vitro high affinity and selectivity toward MAO-A isoenzyme, compared to clorgyline and moclobemide, with Ki values on the picomolar range. Moreover, most of the tested compounds displayed MAO inhibitory effect when tested in vivo. The docking experiments carried out on MAO-A and MAO-B structures proved new information about the enzyme-inhibitor interaction and the potential therapeutic application of 7-oxycoumarin scaffold.

The Schiff base ligand, bis(indoline-2-one)triethylenetetramine (L) obtained from condensation of triethylenetetramine and isatin was used to synthesize the complexes of type, [ML]Cl(2) [M=Co(II), Ni(II), Cu(II) and Zn(II)]. L was characterized on the basis of the results of elemental analysis, FT-IR, (1)H and (13)C NMR, mass spectroscopic studies. The stoichiometry, bonding and stereochemistries of complexes were ascertained on the basis of results of elemental analysis, magnetic susceptibility values, molar conductance and various spectroscopic studies. EPR, UV-vis and magnetic moments revealed an octahedral geometry for complexes. L and its Cu(II) and Zn(II) complexes were screened for their antibacterial activity. Analgesic activity of Cu(II) and Zn(II) complexes was also tested in rats by tail flick method. Both complexes were found to possess good antibacterial and moderate analgesic activity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A series of stiripentol (STP) analogues namely, 2-[(1E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ylidene]-N-(aryl/H)hydrazinecarboxamides 7a-h, (±)-(5RS)-N-(aryl/H)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-carboxamides (±)-8a-h, and (±)-[(5RS)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazol-1-yl](aryl)methanones (±)-13a-f was synthesized by adopting appropriate synthetic routes and was pharmacologically evaluated in the preliminary anticonvulsant screens. The selected bioactive new chemical entities were subjected to ED(50) determination and neurotoxicity evaluation. The most active congeners are 7h in MES screen and (±)-13b in scPTZ screen which displayed ED(50) values of 87 and 110 mg/kg, respectively, as compared to that of STP (ED(50) = 277.7 and 115 mg/kg in MES and scPTZ, respectively)., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

4-aryl-2-amino-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitrile (1), 4-aryl-2-oxo-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitriles (2a-2c), 3-(6-aryl-1,2,5,6- tetrahydro-2-thioxopyrimidin-4-yl)-4-hydroxy-2H-chromen-2-one (3a, 3b) and pyrazol-3-yl-4-hydroxycoumarin derivatives (4a-4c, 5, 6a, 6b, 7a, 7b, and 8a-8c) were prepared in order to measure their % change dopamine release in comparison to amphetamine as reference, using PC-12 cells in different concentrations. In addition, the molecular modeling study of the compounds into 3BHH receptor was also demonstrated. The calculated inhibition constant (k(i)) implemented in the AutoDock program revealed identical correlation with the experimental results to that obtained binding free energy (ΔG(b)) as both parameters revealed reasonable correlation coefficients (R(2)) being 0.51 involving 10 compounds; (1, 2b, 2c, 3a, 3b, 4a, 4b, 6a, and 8c)., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A series of new 9-glycosyl-4,9-dihydropyrano[3,4-b]indole-1(3H)-ones 3 was synthesized in moderate to low yields. 4,9-Dihydropyrano[3,4-b]indole-1(3H)-ones (1) were coupled with different acetobromoglycopyranoses 2 in refluxing toluene in the presence of silver oxide to afford one coupling product of the respective N-glycosides. α-L-Arabinopyranosides 3j and 3m were the most active glycosides among the tested compounds against certain Gram positive and Gram negative bacterial strains.

The main objective of the present work depends on the hybridization of coumarin moiety as a vasorelaxant scaffold and pyrimidine ring with known potential cardiovascular activity in order to prepare some new potent antihypertensive candidates. Hence, two groups of pyrimidinyl coumarin derivatives were synthesized and evaluated for their vasorelaxing activity. These compounds were prepared via two routes; either preparation of the guanidinocoumarin 4 followed by a cocktail of cyclization reactions to yield a different array of 6-(substituted pyrimidin-2-yl)aminocoumarins 5-17, or through cyclization of the precursor chalcones 22a-g with guanidine hydrochloride to generate the corresponding final compounds, 8-(6-aryl-2-aminopyrimidin-4-yl)-7-methoxycoumarins 23a-g. The effect of these compounds and the coumarin intermediates 3, 4, 21 and 22a-g on nor-epinephrine induced contracture in thoracic rat aortic rings was investigated using prazocin as reference drug. Several derivatives showed promising activities either equal or even better than that of prazocin (IC(50) 0.487 mM). The most prospective compounds; the pyrimidinylamino coumarin derivatives 8, 17 (IC(50) 0.411, IC(50) 0.421 mM) and the chalcones 22b, 22e (IC(50) 0.371, 0.374 mM) that displayed the highest activity can be a base for lead optimization and simple but efficient design of new compounds. 2D-QSAR analysis was applied to find a correlation between the experimental vasorelaxant activities of the newly synthesized coumarin derivatives and their different physicochemical parameters. The result of this study showed that the increase in aqueous solubility while retaining good hydrophobic character of the overall molecule is the key for maintaining high relaxation activity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A new series of quinoxaline 1,4-di-N-oxides was synthesized and evaluated for antitumor and hypoxic-selective cytotoxic activities. Antitumor activity against liver carcinoma (Hepg2) and brain tumor (U251) human cell lines were evaluated, among the tested compounds, 5b and 9b exhibited potential cytotoxic effect against Hepg2 with IC50 values of 0.77 and 0.50 microg/mL respectively, whereas, all the tested compounds lack antitumor activity against U251 human cell line. Moreover, compound 4 was the most potent hypoxia selective-cytotoxin on EAC cell line; IC50 2.5 microg/mL, potency 22 microg/mL, and was approximately 5.4-times more selective cytotoxin (HCR>40) than 3-amino-2-quinoxalinecarbonitrile1,4-dioxide (standard, HCR>7.4). Compounds 8b and 9b were more selective than the standard., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

Three series of Spiro [(2H,3H) quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives have been synthesized. Some of the novel quinazolinone derivatives IIe, VIIIc, XIc, XIIb, XIIc, XVIb showed considerable potent anti-inflammatory and analgesic activity of superior G.I.T. safety profile in experimental rats in comparing to indomethacin and tramadol as reference drugs. Docking study into COX-2 has been made for derivatives of highest anti-inflammatory activity. The compound XVIb showed the nearest RMSD value to that of indomethacin., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

The action of the coumarin-type drugs and related compounds is reviewed to their VKOR antagonistic effects. In our study, twenty 3-pyridinyl, pyrimidinyl and pyrazolyl-4-hydroxycoumarin derivatives were synthesized. A comparative in vivo (CT, PT determination) and in vitro (measurement of PIVKA-II levels) anticoagulant study with respect to warfarin showed that the synthesized compounds have different anticoagulant activities, the most prospective compounds were the 3-pyrazolyl-4-hydroxycoumarin derivatives., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A new isatin ribonucleoside (3) was synthesized in a good yield by trimethylsilyl trifluoromethanesulfonate (TMSOTf) catalyzed coupling reaction between the silylated nitrogenated base of 1H-Indole-2,3-dione (1) and 1,2,3,5-tetra-O-acetyl-beta-D-ribfuranose (2). Thiosemicarbazides 4a-e were utilized by the prepared ribonucleoside (3) to give new series of 1H-indole-2,3-dione-3-thiosemicarbazone ribonucleosides 5a-e. All compounds tested as antibacterial agents showed slight inhibitory activity against the selected bacterial strains.

Novel series of bicyclic pyrrolo[1,2-c]pyrimidines 3a-g, 5, 6a, b, and 7a, b, tricyclic pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 8a-c, 9a-g, 13a-c, 17, 18a, b, 19, 20a,b and 21 and tetracyclic condensed pyrimidines 14, 22 and 23 were synthesized through different chemical reactions. Structures of all synthesized pyrimidine derivatives were supported by spectral and elemental analyses. Analgesic activity evaluation was carried out using acetic acid-induced writhing assay, and all compounds exerted comparable activity to indomethacin. The anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema in rats, the potency of the bicyclic derivatives 3a-f and 7b revealed comparable activity to indomethacin without gastric ulceration. The tricyclic derivatives 13a and 20a exerted good activity, however, they induced gastric ulcers while 13b and 13c showed moderate activity without ulceration. In case of tetracyclic derivatives, compound 14 exhibited the highest potency and safety profile.