SUBSTITUENT EFFECT ON THE BINDING MODE AND TOXICITY OF SELECTED 1,4-BENZODIAZEPIN-2-ONE

Extended abstract: 1,4-benzodiazepin-2-ones (BZ) are effective in the treatment of depression, anxiety, epilepsy, insomnia, etc [1]. The structural modifications of 1,4-benzodiazepin-2-ones allow new areas of application due to the change in reactivity, potential binding modes, and stability. A series of eight BZs (Figure 1) has been selected to examine the effect of substituents on the binding energy towards µ-opioid receptor, Lipinski’s rules, and toxicity. Out of many available structures, the selected BZs have four positions in which the substituents were changed [2]. In position R1 an electron-withdrawing (NO2, CN) and electron-donating groups (Cl) are present [2]. The positions R2 and R3 contain H, OH, and CH3 groups. Only bromazepam, a commonly used drug, has nitrogen atom in the second aromatic ring. The structures of selected benzodiazepines were optimized in the Gaussian Program Package at the M06-2X/6-311++G(d,p) level of theory. The molecular docking studies were performed on the µ-opioid receptor (PDB: 4DKL) in AutoDOCK 4.0. The binding site of protein was determined by the presence of morphinan antagonist in the crystal structure. For the toxicity evaluation, the ProTox-II was used. All of the investigated compounds meet Lipinski’s rules of five: the molecular weight below 500 Da, the logP lower than 5, the number of H-bond donors lower than five, and H-bond acceptors lower than 10. When the toxicity is concerned, the selected BZs fall within several categories. Nordiazepam and diazepam have the lowest predicted LD50 dose of 48 mgkg-1, and they belong to the class II compounds which are fatal if swallowed. 7-cyano-1,4-benzodiazepin-2-one has lower toxicity with an LD50 value of 290 mgkg-1 (class III compounds: toxic if swallowed). The ciano group in structure is probably responsible for the hydrogen bond formation with the neighboring amino acids, as examined below. The rest of the compounds belong to the class IV: harmful if swallowed, with LC50 values ranging from 550 (nitrazepam) to 2000 (clonazepam) mgkg-1. The substituent effect on the toxicity is very complex, as all of the investigated compounds have several active positions. The values of binding energies range from -29.3 (bromazepam) to -22.8 (nordiazepam) kJmol-1. Due to the similarity in structure, all of the investigated compounds have similar values of the binding energies and in all cases, this is a favorable process. The presence of an N atom in the second ring structure is an important structural moiety as this is the only feature that differentiates bromazepam from other compounds. The importance of electronegative groups in position R1 is proven in the case of 7-cyano-1,4-benzodiazepin-2-one and nitrazepam. In general, compounds with two electronegative substituents (Cl, NO2, and OH) have higher binding energies. Further research is needed to obtain a detailed structure-activity relationship model that will correlate the substituent properties with toxicity/protein binding affinity.This work was supported by the Ministry of Science and Technological Development of the Republic of Serbia (Contract Nos. 451-03-9/2021-14/200378 and 451-03-9/2021-14/200146)Publishe

ONE-YEAR CARDIOVASCULAR OUTCOME IN PATIENTS ON CLOPIDOGREL ANTI-PLATELET THERAPY AFTER ACUTE MYOCARDIAL INFARCTION

The aim of this study was to determine the risk factors in patients on clopidogrel anti-platelet therapy after acute myocardial infarction, for cardiovascular mortality, re-hospitalization and admission to emergency care unit. We followed 175 patients on dual antiplatelet therapy, with clopidogrel and acetylsalicylic acid, for 1 year after acute myocardial infarction, both STEMI and NSTEMI. Beside demographic and clinical characteristics, genetic ABCB1, CYP2C19 and CYP2C9 profile was analyzed using Cox-regression analysis. End-points used were: mortality, re-hospitalization and emergency care visits, all related to cardiovascular system. During the accrual and follow-up period, 8 patients (4.6%) died, mostly as a direct consequence of an acute myocardial infarction. Re-hospitalization was needed in 27 patients (15.4%), in nine patients (33.3%) with the diagnosis of re-infarction. Thirty-two patients (18.3%) were admitted to emergency care unit due to cardiovascular causes, up to 15 times during the follow-up. NSTEMI was an independent predictor of all three events registered (mortality OR=7.4, p<0.05; re-hospitalization OR=2.8, p<0.05); emergency care visit OR=2.4, p<0.05). Other significant predictors were related to kidney function (urea and creatinine level, creatinine clearance), co-morbidities such as arterial hypertension and decreased left ventricular ejection fraction, as well as clopidogrel dosing regimen. As a conclusion, it may be suggested that one of the most significant predictors of cardiovascular events (mortality, re-hospitalization and emergency care visits) is NSTEMI. Besides, clopidogrel administration according to up-to-date guidelines, with high loading doses and initial doubled maintenance doses, improves 1-year prognosis in patients with AMI

Several coumarin derivatives and their Pd(ii) complexes as potential inhibitors of the main protease of SARS-CoV-2, anin silicoapproach

© The Royal Society of Chemistry 2020. The global pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused many fatalities among people and significantly influenced the global economy. Since efficient treatment is not available, the computational methods in biology and chemistry are a promising starting point towards adequate medication. Three previously synthesized coumarin derivatives and their Pd(ii) complexes were examined for the binding affinity towards the Mproprotein of SARS-CoV-2 by molecular docking and compared to two Food and Drug Administration (FDA) drugs,cinanserinandchloroquine. All of the investigated compounds bind to the active position of the mentioned protein. Coumarin-Pd(ii) complexes showed higher binding affinities compared to the approved drugs. The bindings of the bis(3-(1-((3-chlorophenyl)amino)ethylidene)-chroman-2,4-dione) palladium(ii) complex, its corresponding ligand, andcinanserinto SARS-CoV-2 Mprowere further subjected to the molecular dynamics simulations. The binding free energies, computed by MM/PBSA approach were analyzed in detail and the importance of specific interactions outlined. These results showed that the molecules bearing structural similarity to the approved drugs and their complexes have the potential to inhibit the functional activity of SARS-CoV-2 protease and further experimental studies should be undertaken

Inhibitory activity of quercetin, its metabolite, and standard antiviral drugs towards enzymes essential for SARS-CoV-2: The role of acid-base equilibria

© 2021 The Royal Society of Chemistry. The recently declared global pandemic of a new human coronavirus called SARS-CoV-2, which causes respiratory tract disease COVID-19, has reached worldwide resonance and global efforts are being made to look for possible cures. Sophisticated molecular docking software, as well as available protein sequence and structure information, offer the ability to test the inhibition of two important targets of SARS-CoV-2, furin (FUR) enzyme, and spike glycoprotein, or spike protein (SP), that are key to host cell adhesion and hijacking. The potential inhibitory effect and mechanism of action of acid-base forms of different antiviral drugs, dominant at physiological pH, chloroquine (CQ), hydroxychloroquine (HCQ), and cinanserin (CIN), which have been shown to be effective in the treatment of SARS-CoV-2 virus, is reported with the special emphasis on their relative abundances. On the other hand, the potential inhibitory effect of the dominant acid-base forms of quercetin (Q) and its oxidative metabolite 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H) benzofuranone (BZF), which are constituents of traditional food products believed to exhibit antiviral effects, was also examined. The undertaken study includes the determination of the major energy contributions to the binding energy as well as in-depth analysis of amino acid residues at the active pocket and possible interactions. The approach that we propose here may be an additional strategy for combating the deadly virus by preventing the first step of the virus replication cycle. Preliminary research has shown that the investigated compounds exert an inhibitory effect against the SARS-CoV-2 furin enzyme and spiked glycoprotein through different acid-base forms. These investigations may be helpful in creating potential therapeutic agents in the fight against the SARS-CoV-2 virus. On the other hand, the results we predicted in this computational study may be the basis for new experimental in vitro and in vivo studies. This journal i

Structural characterization of kaempferol: A spectroscopic and computational study

© 2019 Macedonian Journal of Chemistry and Chemical Engineering. Calculations based on the density functional theory, with the B3LYP functional and the 6-311++G(d,p) basis set, were performed with the aim of confirming the molecular structure and spectro-scopic characteristics of kaempferol, a naturally occurring flavonoid molecule. The electronic structure of kaempferol was examined using NBO analysis. The assigning of the experimentally obtained IR and Ra-man spectra was performed after the best-fit-based comparison with theoretical spectra. The 13C and 1H NMR experimental spectra were related to the theoretically obtained values of the chemical shifts deter-mined by the GIAO method. The correlation coefficient and the average absolute error values proved B3LYP-D3 to be an adequate method in describing the NMR parameters of kaempferol. Molecular dock-ing analysis was carried out in order to identify the potency of inhibition of the title molecule against hu-man procalcitonin. The inhibition activity was obtained for 10 conformations of ligand inside the protein

To ventilate or not to ventilate during bystander CPR — A EuReCa TWO analysis

Background: Survival after out-of-hospital cardiac arrest (OHCA) is still low. For every minute without resuscitation the likelihood of survival decreases. One critical step is initiation of immediate, high quality cardiopulmonary resuscitation (CPR). The aim of this subgroup analysis of data collected for the European Registry of Cardiac Arrest Study number 2 (EuReCa TWO) was to investigate the association between OHCA survival and two types of bystander CPR namely: chest compression only CPR (CConly) and CPR with chest compressions and ventilations (FullCPR). Method: In this subgroup analysis of EuReCa TWO, all patients who received bystander CPR were included. Outcomes were return of spontaneous circulation and survival to 30-days or hospital discharge. A multilevel binary logistic regression analysis with survival as the dependent variable was performed. Results: A total of 5884 patients were included in the analysis, varying between countries from 21 to 1444. Survival was 320 (8%) in the CConly group and 174 (13%) in the FullCPR group. After adjustment for age, sex, location, rhythm, cause, time to scene, witnessed collapse and country, patients who received FullCPR had a significantly higher survival rate when compared to those who received CConly (adjusted odds ration 1.46, 95% confidence interval 1.17–1.83). Conclusion: In this analysis, FullCPR was associated with higher survival compared to CConly. Guidelines should continue to emphasise the importance of compressions and ventilations during resuscitation for patients who suffer OHCA and CPR courses should continue to teach both

To ventilate or not to ventilate during bystander CPR : a EuReCa TWO analysis

Background: Survival after out-of-hospital cardiac arrest (OHCA) is still low. For every minute without resuscitation the likelihood of survival decreases. One critical step is initiation of immediate, high quality cardiopulmonary resuscitation (CPR). The aim of this subgroup analysis of data collected for the European Registry of Cardiac Arrest Study number 2 (EuReCa TWO) was to investigate the association between OHCA survival and two types of bystander CPR namely: chest compression only CPR (CConly) and CPR with chest compressions and ventilations (FullCPR). Method: In this subgroup analysis of EuReCa TWO, all patients who received bystander CPR were included. Outcomes were return of spontaneous circulation and survival to 30-days or hospital discharge. A multilevel binary logistic regression analysis with survival as the dependent variable was performed. Results: A total of 5884 patients were included in the analysis, varying between countries from 21 to 1444. Survival was 320 (8%) in the CConly group and 174 (13%) in the FullCPR group. After adjustment for age, sex, location, rhythm, cause, time to scene, witnessed collapse and country, patients who received FullCPR had a significantly higher survival rate when compared to those who received CConly (adjusted odds ration 1.46, 95% confidence interval 1.17–1.83). Conclusion: In this analysis, FullCPR was associated with higher survival compared to CConly. Guidelines should continue to emphasise the importance of compressions and ventilations during resuscitation for patients who suffer OHCA and CPR courses should continue to teach both

Cardiopulmonary resuscitation in adults over 80 : outcome and the perception of appropriateness by clinicians

OBJECTIVES: To determine the prevalence of clinician perception of inappropriate cardiopulmonary resuscitation (CPR) regarding the last out‐of‐hospital cardiac arrest (OHCA) encountered in an adult 80 years or older and its relationship to patient outcome. DESIGN: Subanalysis of an international multicenter cross‐sectional survey (REAPPROPRIATE). SETTING: Out‐of‐hospital CPR attempts registered in Europe, Israel, Japan, and the United States in adults 80 years or older. PARTICIPANTS: A total of 611 clinicians of whom 176 (28.8%) were doctors, 123 (20.1%) were nurses, and 312 (51.1%) were emergency medical technicians/paramedics. RESULTS AND MEASUREMENTS: The last CPR attempt among patients 80 years or older was perceived as appropriate by 320 (52.4%) of the clinicians; 178 (29.1%) were uncertain about the appropriateness, and 113 (18.5%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the “appropriate” subgroup was 8 of 265 (3.0%), 1 of 164 (.6%) in the “uncertain” subgroup, and 2 of 107 (1.9%) in the “inappropriate” subgroup (P = .23); 503 of 564 (89.2%) CPR attempts involved non‐shockable rhythms. CPR attempts in nursing homes accounted for 124 of 590 (21.0%) of the patients and were perceived as appropriate by 44 (35.5%) of the clinicians; 45 (36.3%) were uncertain about the appropriateness; and 35 (28.2%) perceived the CPR attempt as inappropriate. The survival to hospital discharge for the nursing home patients was 0 of 107 (0%); 104 of 111 (93.7%) CPR attempts involved non‐shockable rhythms. Overall, 36 of 543 (6.6%) CPR attempts were undertaken despite a known written do not attempt resuscitation decision; 14 of 36 (38.9%) clinicians considered this appropriate, 9 of 36 (25.0%) were uncertain about its appropriateness, and 13 of 36 (36.1%) considered this inappropriate. CONCLUSION: Our findings show that despite generally poor outcomes for older patients undergoing CPR, many emergency clinicians do not consider these attempts at resuscitation to be inappropriate. A professional and societal debate is urgently needed to ensure that first we do not harm older patients by futile CPR attempts. J Am Geriatr Soc 68:39–45, 201