SYNTHESIS, ANTICANCER ACTIVITY AND MOLECULAR DOCKING STUDY OF NOVEL 1, 3-DIHETEROCYCLES INDOLE DERIVATIVES

Objective: The present work aimed to synthesize some new 1, 3-diheterocyles indolyl derivatives and study their cytotoxic activity. In addition, explore the probability of the most promising antiproliferative compounds to inhibit TopoI enzyme theoretically via molecular docking study.Methods: Reaction of ethyl 2-(3-formyl-1H-indol-1-yl)acetate (1) with 2-cyanoacetic acid hydrazide, 3-amino-5-pyrazolone and 2'-acetyl-2-cyanoacetohydrazide in an equal molar ratio led to the formation of compounds 2, 6, 8 and 10, respectively, which in turn reacted with another molecule of 2-cyanoacetic acid hydrazide and/or 3-amino-5-pyrazolone (1:1 molar ratio) to give novel series of 1,3-dipyrazole indole derivatives 3, 7, 9 and 11, respectively. On the other hand, Knoevenagel condensation of 1 with malononitrile gave ethyl 2-(3-(2, 2-dicyanovinyl)-1H-indol-1-yl) acetate (11). Reaction of 11 with 2-cyanoacetic acid hydrazide, 3-amino-5-pyrazolone, hydrazine hydrate, urea, thiourea and/or guanidine yielded 1, 6-diaminopyridine 12, pyrano(2,3-c)pyrazole 14, pyrazole 16 and pyrimidine derivatives 18a-c, respectively. Reaction of the latter compounds with 3-amino-5-pyrazolone furnished a novel series of 1, 3-diheterocycle indole derivatives 13, 15, 17 and 19a-c, respectively. Ten new target compounds 3, 6, 8, 10, 13, 15, 17 and 19a-c were tested for in vitro antiproliferative activity against A-549, MCF7, HCT-116 and HEPG2 cancer cell lines. In addition, molecular docking study of the most promising antiproliferative compounds against human DNA Topoisomerase I (PDB ID: 1T8I) theoretically is discussed.Results: Compounds 3, 6, 8 and 17 showed potent in vitro antiproliferative activity. Docking scores of the latter compounds were observed better than co-crystalline ligand.Conclusion: Further work is recommended to confirm the inhibition of TopoI in a specific bioassay

SYNTHESIS AND ANTIVIRAL ACTIVITY OF NOVEL ETHYL 2-(3-HETEROCYCLE-1H-INDOL-1-YL) ACETATE DERIVATIVES

Objective: Marek's disease (MD) is a widespread, herpesvirus-induced neoplastic disease in the domestic chicken that is caused by Marek's disease virus (MDV). Marek’s disease virus (MDV) belongs to the alphaherpesvirus family such as Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2). Recently Bag and co-workers 2014 reported that, 7-methoxy-1-methyl-4, 9-dihydro-3H-pyrido [3, 4-b]indole (Harmaline) showed potent anti-HSV-1 activity against both wild type and clinical isolates of HSV-1. The present work aimed to synthesize some new heterocyclic systems incorporated to indole moiety starting from ethyl 2-(3-acetyl-1H-indol-1-yl)acetate (1) in order to evaluate their antiviral activity in a trail to explore potential antiviral agents against MDV to limit the disease course and losses. Methods: Reaction of ethyl 2-(3-acetyl-1H-indol-1-yl) acetate (1) with semicarbazide hydrochloride yielded semicarbazone derivative 2. The oxidative cyclization of 2 using thionyl chloride and selenium dioxide afforded 1, 2, 3-thia and 1, 2, 3-selenadiazole derivatives 3 and 4, respectively. On the other hand, reaction of 1 with 4-chloro and 4-nitrobenzaldehydes under Claisen-Schmidt conditions gave α, β-unsaturated keto derivatives 5a, b. Cyclization of 5a, b using hydrazine hydrate, phenyl hydrazine, urea, thiourea or guanidine led to the formation of pyrazoles 6a, b, 7a, b, and pyrimidines derivatives 8a, b-10a, b; respectively. Condensation of 1 with phenyl hydrazine followed by Vilsmeier Haack formylation gave pyrazole-4-carboxaldehyde derivative 12. Reaction of aldehydic function group of 12 with different reagents led to the formation of pyrazol-5-ones 14-16, thiazolidinone 18, aziditine 19, 1, 6-diaminopyridine 21, triazolo(1, 5-a)pyridine 22 and pyrano(2, 3-c) pyrazole derivatives 23. The in vitro antiviral activity of the selected compounds 6a, b 7a, b 8a, b 9a, b and 10a, b was studied against Marek's disease virus (MDV). Results: Chicken embryo experiment showed that compounds 7b, 8b, 9b and 10a possessed significant antiviral activity with IC50 ranged between 5 and 6 µg/ml and substantial therapeutic indices (TI) of 80 and 83 were recorded. Cytotoxicity assay indicated that CC50 of 7b, 8b, 9b and 10 were greater than 400 and 500 mg/ml. Conclusion: Compounds 7b, 8b, 9b and 10a showed promising effect as anti-MDV infectivity application

Sinteza, antimikrobno i antitumorsko djelovanje nekoliko novih N-etil, N-benzil i N-benzoil-3-indolil heterocikličkih spojeva

A series of 1-(N-substituted-1H-indol-3-yl)-3-arylprop-2-ene-1-ones (2a,b-4a,b) were prepared and allowed to react with urea, thiourea or guanidine to give pyrimidine derivatives 5a,b–13a,b. Reaction of 2a,b-4a,b with ethyl acetoacetate in the presence of a base gave cyclohexanone derivatives 14a,b-16a,b. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 17a,b-19a,b. On the other hand, reaction of 2a,b-4a,b with some hydrazine derivatives, namely hydrazine hydrate, acetyl hydrazine, phenyl- hydrazine and benzylhydrazine hydrochloride, led to the formation of pyrazole derivatives 20a,b-31a,b. Moreover, reaction of 2a,b-4a,b with hydroxylamine hydrochloride gave isoxazole derivatives 32a,b-34a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that 4-(N-ethyl-1H-indol-3-yl)-6-(p-chlorophenyl)-pyrimidine-2-amine (11b) was the most active of all the test compounds towards Candida albicans compared to the reference drug cycloheximide. Eighteen new compounds, namely pyrimidin-2(1H)-ones 5a,b-7a,b, pyrimidin-2(1H)-thiones 8a,b-10a,b and pyrimidin-2-amines 11a,b-13a,b derivatives, were tested for their in vitro antiproliferative activity against HEPG2, MCF7 and HCT-116 cancer cell lines. 4-(N-ethyl-1H-indol-3-yl)-6-(p-methoxyphenyl)-pyrimidin-2-amine (11a) was found to be highly active with IC50 of 0.7 µmol L1.Sintetizirana je serija 1-(N-supstituiranih-1H-indol-3-il)-3-arilprop-2-en-1-ona (2a,b-4a,b) i podvrgnuta reakciji s ureom, tioureom ili gvanidinom, pri čemu su nastali derivati pirimidina 5a,b–13a,b. Reakcijom 2a,b-4a,b s etil-acetoacetatom u prisutnosti baze nastali su derivati cikloheksanona 14a,b-16a,b. Njihovom reakcijom s hidrazin hidratom dobiveni su derivati indazola 17a,b-19a,b. S druge strane, reakcijom 2a,b-4a,b s određenim derivatima hidrazina, tj. s hidrazin hidratom, acetil hidrazinom, fenilhidrazinom i benzilhidrazin hidrokloridom, nastali su derivati pirazola 20a,b-31a,b. Nadalje, reakcijom 2a,b-4a,b s hidroksilamin hidrokloridom dobiveni su derivati izoksazola 32a,b-34a,b. Pripravljeni spojevi ispitani su na antimikrobno djelovanje. Pokazalo se da je 4-(N-etil-1H-indol-3-il)-6-(p-klorfenil)-pirimidin-2-amin (11b) najaktivniji spoj za Candida albicans (ATCC 10231) uz cikloheksimid kao poredbeni lijek. Testirano je antitumorsko djelovanje in vitro osamnaest novih spojeva, tj. pirimidin-2(1H)-ona 5a,b-7a,b, pirimidin-2(1H)-tiona 8a,b-10a,b i pirimidin-2-amina 11a,b-13a,b na tumorske stanice HEPG2, MCF7 i HCT-116. Najaktivniji spoj bio je 4-(N-etil-1H-indol-3-il)-6-(p-metoksifenil)-pirimidin-2-amin (11a) uz IC50 0,7 µmol L1

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Antitumor activity of intratracheal inhalation of temozolomide (TMZ) loaded into gold nanoparticles and/or liposomes against urethane-induced lung cancer in BALB/c mice

The current study aimed to develop gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) as drug carriers for temozolomide (TMZ) and investigate the possible therapeutic effects of intratracheal inhalation of nanoformulation of TMZ-loaded gold nanoparticles (TGNPs) and liposome-embedded TGNPs (LTGNPs) against urethane-induced lung cancer in BALB/c mice. Physicochemical characters and zeta potential studies for gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) were performed. The current study was conducted by inducing lung cancer chemically via repeated exposure to urethane in BALB/C mice. GNPs and LGNPs were exhibited in uniform spherical shape with adequate dispersion stability. GNPs and LGNPs showed no significant changes in comparison to control group with high safety profile, while TGNPs and LTGNPs succeed to improve all biochemical data and histological patterns. GNPs and LGNPs are promising drug carriers and succeeded in the delivery of small and efficient dose of temozolomide in treatment lung cancer. Antitumor activity was pronounced in animal-treated LTGNPs, these effects may be due to synergistic effects resulted from combination of temozolomide and gold nanoparticles and liposomes that may improve the drug distribution and penetration

Synthesis, Molecular Docking, and Biofilm Formation Inhibitory Activity of Bis(Indolyl)Pyridines Analogues of the Marine Alkaloid Nortopsentin

An efficient and simple protocol for the synthesis of a new class of diverse bis(indolyl)pyridines analogues of the marine alkaloid nortopsentin has been reported. A one-pot four-component condensation of 3-cyanocarbomethylindole, various aldehyde, 3-acetylindole, and ammonium acetate in glacial acetic acid led to the formation of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridine-5-carbonitriles. Additionally, 2,6-bis(1H-indol-3-yl)-4-(benzofuran) pyridine-5-carbonitriles were prepared via a one-pot four-component condensation of 3-cyanocarbomethylindole, various N-substituted-indole-3-aldehydes, 2-acetylbenzofuran, and ammonium acetate. The synthesized compounds were evaluated for their ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 6538 and the Gram-negative strain Escherichia coli ATCC 25922. Some of the new compounds showed a marked selectivity against the Gram-positive and Gram-negative strains. Remarkably, five compounds 4b, 7a, 7c, 7d and 8e demonstrated good antibiofilm formation against S. aureus and E. coli. On the other hand, the release of reducing sugars and proteins from the treated bacterial strains over the untreated strains was considered to explain the disruption effect of the selected compound on the contact cells of S. aureus and E. coli. Out of all studied compounds, the binding energies and binding mode of bis-indole derivatives 7c and 7d were theoretically the best thymidylate kinase, DNA gyrase B and DNA topoisomerase IV subunit B inhibitors

SYNTHESIS, ANTIMICROBIAL ACTIVITY AND MOLECULAR DOCKING STUDY OF SOME NEW N-BENZYL AND N-BENZOYL-3-INDOLYL HETEROCYCLES

Objective: Chalcones are one of the major classes of the natural products, which display a wide range of pharmacological properties. Also, chalcones are well-known intermediates for synthesizing various heterocyclic compounds like pyrazoline and pyrimidine derivatives. The present work is designed to synthesize new 3-indolylheterocycles starting from N-benzyl and N-benzoyl-1H-indole-3-carboxaldehyds and evaluating theirs in vitro antimicrobial activity. In addition, the probability of the most promising antimicrobial compounds to inhibit ATPase, enoyl reductase and dihydrofolate reductase were studied theoretically via molecular docking.Methods: A new series of 3-indolylchalcones 2a,b were prepared and allowed to react with hydrazine hydrate, phenyl hydrazine, hydroxylamine, urea, thiourea and guanidine to afford the corresponding pyrazoles 3a,b-6a,b and pyrimidines derivatives 7a,b-9a,b. On the other hand, the reaction of 2a, b with malononitrile afforded 10a, b, which upon cyclo-condensation with formic acid, formamide, urea or thiourea yielded the fused pyrido [2,3-d]pyrimidine 11a,b-14a,b. Moreover, cyclo-condensation of 2a, b with thiosemicarbazide gave pyrazolin-1-carbothioamides 15a, b, which under cyclization with phenacyl bromide afforded thiazole derivatives 16a and 16b. While the reaction of 2a, b with cyano thioacetamide afforded 2-mercaptonicotinonitriles 17a, b. The reaction of 17a, b with some halo-compounds gave S-alkyl derivatives 18a-d and 19a-d, respectively,which under heating in the presence of piperidine gave the fused thienopyridines 20a-d and 21a-d, respectively. All the newly prepared compounds were evaluated for their in vitro antimicrobial activity. In addition, molecular docking study of the most promising antimicrobial compounds against ATPase, enoyl reductase and dihydrofolate reductase theoretically is discussed.Results: Compounds 17a and 17b were found to be the most potent compounds with MIC of 0.98, 0.49 and 0.98µg/ml against S. pneumoniae (RCMB 010010), E. coli (RCMB 010052) and A. fumigatus (RCMB 02568), respectively compare to the reference drugs. Also, compounds 17a and 17b exhibited good docking scores and could act as inhibitors of enzymes understudied.Conclusion: Further work is recommended to confirm the ability of compounds 17a and 17b to inhibit ATPase, enoyl reductase and dihydrofolate reductase in a specific bioassay