Sinteza, protuupalno, analgetsko i antikonvulzivno djelovanje 1,8-dihidro-1-aril-8-alkil pirazolo(3,4-b)indola

A series of 1,8-dihydro-1-aryl-8-alkyl pyrazolo(3,4-b)indoles 4a-j, 5a-j and 6a-j has been synthesized and tested for their anti-inflammatory and anticonvulsant activities. Formation of the pyrazoloindole derivatives was achieved by treating arylhydrazones of N-alkyl indole-3-carboxaldehydes 1a-j, 2a-j and 3a-j with ten times their mass of polyphosphoric acid as a condensing agent. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic and anticonvulsant activities compared to indomethacin, flufenamic acid and diazepam as positive controls. Detailed synthesis, spectroscopic and toxicity data are reported.Serija 1,8-dihidro-1-aril-8-alkil pirazolo(3,4-b)indola 4a-j, 5a-j i 6a-j sintetizirana je i testirana na protuupalno i antikonvulzivno djelovanje. Pirazolindol derivati pripravljeni su reakcijom arilhidrazona N-alkil indol-3-karboksaldehida 1a-j, 2a-j i 3a-j s deset puta većom masom polifosforne kiseline kao sredstva za kondenzaciju. Novosintetizirani spojevi testirani su na protuupalno, analgetsko i antikonvulzivno djelovanje i uspoređeni s djelovanjem indometacina, flufenaminske kiseline i diazepama. U radu su dati detaljni sintetski, spektroskopski i toksikološki podaci

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 i biološko djelovanje novih 1-benzil i 1-benzoil 3-heterocikličkih derivata indola

Starting from 1-benzyl- (2a) and 1-benzoyl-3-bromoacetyl indoles (2b) new heterocyclic, 2-thioxoimidazolidine (4a,b), imidazolidine-2,4-dione (5a,b), pyrano(2,3-d)imidazole (8a,b and 9a,b), 2-substituted quinoxaline (11a,b–17a,b) and triazolo(4,3-a)quinoxaline derivatives (18a,b and 19a,b) were synthesized and evaluated for their antimicrobial and anticancer activities. Antimicrobial activity screening performed with concentrations of 0.88, 0.44 and 0.22 g mm2 showed that 3-(1-substituted indol-3-yl)quinoxalin-2(1H)ones (11a,b) and 2-(4-methyl piperazin-1-yl)-3-(1-substituted indol-3-yl) quinoxalines (15a,b) were the most active of all the tested compounds towards P. aeruginosa, B. cereus and S. aureus compared to the reference drugs cefotaxime and piperacillin, while 2-chloro-3-(1-substituted indol-3-yl)quinoxalines (12a,b) were the most active against C. albicans compared to the reference drug nystatin. On the other hand, 2-chloro-3-(1-benzyl indol-3-yl) quinoxaline (12a) display potent efficacy against ovarian cancer xenografts in nude mice with tumor growth suppression of 100 0.3 %.U radu je opisana sinteza, antimikrobno i antitumorsko djelovanje heterocikličkih derivata indola. Polazeći iz 1-benzil- i 1-benzoil-3-bromacetil indola (2a i 2b) sintetizirani su novi heterociklički spojevi 2-tioksoimidazolidini (4a,b), imidazolidin-2,4-dioni (5a,b), pirano(2,3-d)imidazoli (8a,b i 9a,b), 2-supstituirani kinoksalini (11a,b–17a,b) i triazolo(4,3-a)kinoksalini (18a,b i 19a,b). Sintetizirani spojevi testirani su na antimikrobno i antitumorsko djelovanje. Ispitivanje antimikrobnog djelovanja provedeno je s koncentracijama otopina 0,88, 0,44 i 0,22 g mm2 i uspoređeno s referentnim lijekovima cefotaksimom i piperacilinom. Rezultati pokazuju da su 3-(1-supstituirani indol-3-il)kinoksalin-2(1H)oni (11a,b) i 2-(4-metil piperazin-1-il)-3-(1-supstituirani indol-3-il) kinoksalini (15a,b) najaktivniji spojevi na sojeve P. aeruginosa, B. cereus i S. aureus, dok su 2-klor-3-(1-supstituirani indol-3-il)kinoksalini (12a,b) najaktivniji na C. albicans (usporedba s nistatinom). Osim toga, 2-klor-3-(1-benzil indol-3-il) kinoksalin (12a) pokazuje veliku učinkovitost na tumore ovarija miševa (supresija rasta tumora 100 0,3 %)

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

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p&lt;0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p&lt;0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin(benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin(benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020