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

LEARN: A multi-centre, cross-sectional evaluation of Urology teaching in UK medical schools

OBJECTIVE: To evaluate the status of UK undergraduate urology teaching against the British Association of Urological Surgeons (BAUS) Undergraduate Syllabus for Urology. Secondary objectives included evaluating the type and quantity of teaching provided, the reported performance rate of General Medical Council (GMC)-mandated urological procedures, and the proportion of undergraduates considering urology as a career. MATERIALS AND METHODS: LEARN was a national multicentre cross-sectional study. Year 2 to Year 5 medical students and FY1 doctors were invited to complete a survey between 3rd October and 20th December 2020, retrospectively assessing the urology teaching received to date. Results are reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). RESULTS: 7,063/8,346 (84.6%) responses from all 39 UK medical schools were included; 1,127/7,063 (16.0%) were from Foundation Year (FY) 1 doctors, who reported that the most frequently taught topics in undergraduate training were on urinary tract infection (96.5%), acute kidney injury (95.9%) and haematuria (94.4%). The most infrequently taught topics were male urinary incontinence (59.4%), male infertility (52.4%) and erectile dysfunction (43.8%). Male and female catheterisation on patients as undergraduates was performed by 92.1% and 73.0% of FY1 doctors respectively, and 16.9% had considered a career in urology. Theory based teaching was mainly prevalent in the early years of medical school, with clinical skills teaching, and clinical placements in the later years of medical school. 20.1% of FY1 doctors reported no undergraduate clinical attachment in urology. CONCLUSION: LEARN is the largest ever evaluation of undergraduate urology teaching. In the UK, teaching seemed satisfactory as evaluated by the BAUS undergraduate syllabus. However, many students report having no clinical attachments in Urology and some newly qualified doctors report never having inserted a catheter, which is a GMC mandated requirement. We recommend a greater emphasis on undergraduate clinical exposure to urology and stricter adherence to GMC mandated procedures

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Survival after Combined Hepatic Metastasectomy and Chemotherapy in Patients with Concurrent Hepatic and Extrahepatic Colorectal Metastases: a SEER Database Analysis

Abstract PurposeColorectal cancer is the second leading cause of death among all cancers worldwide. Hepatic metastases exist in approximately 50% of colorectal cancer patients. The purpose of this study was to assess the effect of combined hepatic metastasectomy and chemotherapy on overall survival in patients with concurrent hepatic and extrahepatic disease.MethodsA total of 2533 patients from the US Surveillance, Epidemiology, and End Results (SEER) database with concurrent colorectal liver metastasis (CRLM) and extrahepatic disease (EHD) between January 1, 2010, and December 31, 2014, were retrieved. Survival analysis with Kaplan-Meier and Cox regression analyses was performed to assess the effect of combined hepatic metastasectomy and chemotherapy on 5-year survival.ResultsTwo hundred and fourteen (8.4%) patients underwent combined hepatic metastasectomy and chemotherapy. The median survival time among patients who underwent combined hepatic metastasectomy and chemotherapy was significantly higher than that of patients who underwent chemotherapy alone (24 vs. 21 months; p &lt; 0.0001). Furthermore, older age at diagnosis (≥ 60 years), American Indian/Alaska Native race, primary sites at the rectosigoid colon, sigmoid colon, and descending colon, grade III, and the presence of bone metastases were all significantly associated with higher 5-year mortality. Patients who underwent combined hepatic metastasectomy and chemotherapy were significantly associated with 22.2% less 5-year mortality than patients who received chemotherapy alone.ConclusionCombined hepatic metastasectomy with chemotherapy in CRLM patients with EHD yields better survival than chemotherapy alone.</jats:p

Survival After Combined Hepatic Metastasectomy and Chemotherapy in Patients with Concurrent Hepatic and Extrahepatic Colorectal Metastases: A SEER Database Analysis.

Abstract Purpose: Colorectal cancer is the second leading cause of death among all cancers worldwide. Hepatic metastases exist in about 50% of colorectal cancer patients. The purpose of this study was to assess the effect of combined hepatic metastasectomy and chemotherapy on the overall survival in patients with concurrent hepatic and extra-hepatic disease.Methods: 2533 patients from the US Surveillance, Epidemiology, and End Results (SEER) database with concurrent colorectal liver metastasis (CRLM) and extra-hepatic disease (EHD) between January 1, 2010, and December 31, 2014, were retrieved. Survival analysis with Kaplan-Meier and Cox-regression was performed to assess the effect of combined hepatic metastasectomy and chemotherapy on 5-year survival. Results: Two-hundred and fourteen (8.4%) patients underwent combined hepatic metastasectomy and chemotherapy. The median survival time among patients underwent combined hepatic metastasectomy, and chemotherapy was significantly higher than chemotherapy alone (24 vs. 21 months; p &lt; 0.0001). Furthermore, older age at diagnosis (≥ 60 years), American Indian/Alaska Native race, primary sites at the recto-sigmoid colon, sigmoid colon, and descending colon, grade III, and the presence of bone metastases were all significantly associated with higher 5-year mortality. Patients who underwent combined hepatic metastasectomy and chemotherapy were significantly associated with 22.2% less 5-year mortality compared to patients who received chemotherapy alone. Conclusion: Combined hepatic metastasectomy with chemotherapy in CRLM patients with EHD yields better survival than chemotherapy only.</jats:p

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

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;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 &lt;em&gt;N&lt;/em&gt;-benzyl and &lt;em&gt;N&lt;/em&gt;-benzoyl-1&lt;em&gt;H&lt;/em&gt;-indole-3-carboxaldehyds and evaluating theirs &lt;em&gt;in vitro&lt;/em&gt; antimicrobial activity. In addition, the probability of the most promising antimicrobial compounds to inhibit ATPase, enoyl reductase and dihydrofolate reductase were studied theoretically &lt;em&gt;via &lt;/em&gt;molecular docking.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods&lt;/strong&gt;&lt;strong&gt;:&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;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-&lt;em&gt;d&lt;/em&gt;]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 &lt;em&gt;in vitro&lt;/em&gt; antimicrobial activity. In addition, molecular docking study of the most promising antimicrobial compounds against ATPase, enoyl reductase and dihydrofolate reductase theoretically is discussed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Compounds 17a and 17b were found to be the most potent compounds with MIC of 0.98, 0.49 and 0.98µg/ml against &lt;em&gt;S.&lt;/em&gt;&lt;em&gt; &lt;/em&gt;&lt;em&gt;pneumoniae&lt;/em&gt;&lt;em&gt; &lt;/em&gt;(RCMB 010010), &lt;em&gt;E&lt;/em&gt;&lt;em&gt;. coli &lt;/em&gt;(RCMB 010052) and &lt;em&gt;A.&lt;/em&gt; &lt;em&gt;fumigatus&lt;/em&gt; (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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;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.&lt;/p&gt;</jats:p

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