Synthesis, biological activity and POM/DFT/docking analyses of annulated pyrano[2,3-d]pyrimidine derivatives: Identification of antibacterial and antitumor pharmacophore sites.

New annulated pyrano[2,3-d]pyrimidine derivatives were synthesized with hydroxyl, methoxy, bromine, nitrile and nitro substituents on its skeleton. The correlated electronic effect of substituents on the magnitude of antibacterial activity was noted. The electron donating substituents (namely; 4-OH, 4-OCH3, 4-Br) and electron withdrawing substituents (4-NO2) on phenyl ring in the pyrano[2,3-d]pyrimidine skeleton exerted different influence on its antimicrobial activity against some Gram-positive and Gram-negative bacteria such as Pseudomonas aureus, E. coli, Staphylococcus aureus, Klebsiella pneumonia and Bacillus cereus. All the pyrano[2,3-d]pyrimidines were characterized by spectroscopic analyses. Antibacterial screening revealed that the presence of heteroaryl, cyano and amino groups on pyrano[2,3-d]pyrimidine skeleton increases its penetrating power on the bacterial cell wall so that the product becomes more biologically active. So the the nature of electron withdrawing or electro-donnor Impact of substituents should be taken in consideration in drug design. Hydrolysis of -CRN to amide restored vital Intramolecular interaction like ortho-nitrophenyl and ONOδ-…NHδ+/amide link, offering a crucial template for antibacterial NH, HO-pharmacophore sites, which ultimately elevated innate antimicrobial profiles. POM combinatorial analysis of tangible electronic contributions due to armed annulated pyrano[2,3-d]pyrimidines concluded their broad antimicrobial activity and viable/prominent drug score index through perspective parameters particularly: inter atomic distance/linkers, steric, electronic, polar parameters, and with a different polarising effect of electron donating/withdrawing environments of substituents. Furthermore, an anti-Kinase pharmacophore site (OCNHCO) was evaluated in continuation of the POM investigations. All synthesized products verified fewer side effects than standard streptomycin, but facile implication in selective cancer media (viz. breast or leucemia still needs to be screened).

Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors.

Inhibitors of human lactate dehydrogenase (hLDH5)-the enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD⁺-are promising therapeutic agents against cancer because this enzyme is generally found to be overexpressed in most invasive cancer cells and is linked to their vitality especially under hypoxic conditions. Consequently, significant efforts have been made for the identification of small-molecule hLDH5 inhibitors displaying high inhibitory potencies. X-ray structure of hLDH5 complexes as well as molecular modeling studies contribute to identify and explain the main binding modes of hLDH5 inhibitors reported in literature. The purpose of this review is to analyze the main three-dimensional interactions between some of the most potent inhibitors and hLDH5, in order to provide useful suggestions for the design of new derivatives.

The long-term impact of early cardiovascular therapy intensification for postoperative troponin elevation after major vascular surgery.

BACKGROUND: Acute cardiac events are a frequent cause of morbidity after vascular surgery. The impact of early evidence-based treatment for patients with an acute cardiac event after vascular surgery on long-term postoperative outcomes has not been extensively studied. We hypothesized that providing appropriate evidence-based treatment to patients with elevated postoperative cardiac troponin levels may limit long-term mortality. METHODS: We conducted a study of 667 consecutive major vascular surgery patients with an elevated postoperative troponin I level. We then determined which of these patients received medical therapy as per the 2007 American College of Cardiology/American Heart Association recommendations for the medical management of patients with chronic stable angina. All patients with troponin elevation were then matched with 2 control patients without postoperative troponin elevation. Matching was done using logistic regression and nearest-neighbor matching methods. The primary study end point was 12 months survival without a major cardiac event (i.e., death, myocardial infarction, coronary revascularization, or pulmonary edema requiring hospitalization). RESULTS: Therapy was intensified in 43 of 66 patients (65%) who suffered a troponin I elevation after surgery. Patients with a troponin I elevation not receiving intensified cardiovascular treatment had a hazard ratio (HR) of 1.77 (95% confidence interval (CI), 1.13-2.42; P = 0.004) for the primary study outcome as compared with the control group. In contrast, patients with a troponin I elevation who received intensified cardiovascular treatment had an HR of 0.63 (95% CI, 0.10-1.19; P = 0.45) for the primary outcome as compared with the control group. Patients with a troponin I elevation not receiving treatment intensification likely were at higher risk for a major cardiac event (HR, 2.80; 95% CI, 1.05-24.2; P = 0.04) compared with patients who did receive treatment intensification. CONCLUSIONS: The main finding of this study was that in patients with elevated troponin I levels after noncardiac surgery, long-term adverse cardiac outcomes may likely be improved by following evidence-based recommendations for the medical management of acute coronary syndromes.

In vitro antitumor activity, molecular dynamics simulation, DFT study, ADME prediction, and Eg5 binding of enastron analogues.

The objective of this study is to evaluate a series of molecules based on cyclosulfamide as potential anticancer agents. Additionally, the study aims to analyze the obtained results through in silico studies; by conducting experiments and utilizing theoretical methods. In this context, we investigated the cytotoxic activity of enastron analogues on three human cell lines PRI (lymphoblastic cell line) derived from B-cell lymphoma. JURKAT (ATCC TIB-152) acute T cell leukaemia and K562 (ATCC CLL-243) is a chronic myelogenous leukaemia. Most of the tested compounds showed good inhibitory activity compared with the reference ligand (chlorambucil). The 5a derivative demonstrated the strongest effect against all cancer cells used. Furthermore, molecular docking simulations of the Eg5-enastron analogue complex revealed that studied molecules have the ability to inhibit the Eg5 enzyme, as evidenced by their calculated docking score. Following the promising results from the molecular docking study, the complex Eg5-4a underwent a 100 ns molecular dynamics simulation using Desmond. During the simulation, the receptor-ligand pairing demonstrated substantial stability after the initial 70 ns. In addition, we used DFT calculations to analyze the electronic and geometric characteristics of the studied compounds. The HOMO and LUMO band gap energies, and the molecular electrostatic potential surface were also deducted for the stable structure of each compound. Also, we studied the prediction of absorption, distribution, metabolism and excretion (ADME) of the compounds.

Novel N-acylsulfonamides: Synthesis, in silico prediction, molecular docking dynamic simulation, antimicrobial and anti-inflammatory activities.

Microbial resistance to drugs currently traded in the market is a serious problem in modern medicine. In this field of research, we synthesized a novel N-acylsulfonamides (NAS) derivatives starting from commercially available compounds; morpholine, isocyanate of chlorosulfonyl and alcohols. The in vitro antimicrobial potential of synthesized compounds was screened against 04 Gram-negative bacteria; Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, 02 Gram-positive bacteria: Streptococcus sp, Staphylococcus aureus and 07 yeasts and fungi: Candida albicans, Candida spp, Penicillum spp, Aspegillus sp, Aspergillus flavus, Fusarium sp, and Cladosporium spp. The results of inhibition growth were compared with standard antimicrobial drugs with the goal of exploring their potential antimicrobial activity. In addition, the anti-inflammatory activity of the synthesized compounds was determined in-vitro by protein denaturation method. The obtained bioactivity results were further validated by in silico DFT (Density Functional Theory), ADME (Absorption-Distribution-Métabolisation-Excrétion), molecular docking studies and molecular dynamics simulations.Communicated by Ramaswamy H. Sarma.

Efficacy of low-dose oral sulodexide in the management of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the single greatest cause of end-stage renal disease (ESRD). Without specific interventions, microalbuminuria (incipient nephropathy) gradually progresses to macroalbuminuria (overt nephropathy) within 10-15 years in about 80% of type 1 and 30% of type 2 diabetic patients, and to ESRD within further 20 years in about 75% and 20%, respectively. A primary alteration in DN consists of decreased concentration of glycosaminoglycans (GAGs) in the glomerular extracellular matrix. This evidence has prompted interest in using exogenous GAGs and specifically sulodexide in DN treatment. PATIENTS AND METHODS: In this uncontrolled multicenter study, diabetic patients with albumin excretion rate (AER) >or=30 mg/24 hours were treated with oral sulodexide 50 mg/day for 6 months, while receiving concomitant medication as required. Two hundred thirty-seven patients (54% males and 46% females, mean age 55 years, mean diabetes duration 11 years) were evaluated; 89% had type 2 and 11% type 1 diabetes mellitus, 67% microalbuminuria and 33% macroalbuminuria. RESULTS: AER was significantly and progressively reduced during sulodexide treatment (p<0.0001): geometric mean after 3 and 6 months was 63.7% (95% confidence interval [95% CI], 59.3%-68.4%) and 42.7% (95% CI, 37.8%-48.2%) of baseline, respectively. The reduction was similar in type 1 and type 2 diabetes and was slightly greater in macroalbuminuric than in microalbuminuric patients. Blood pressure was slightly lowered, while fasting glucose and glycosylated hemoglobin were moderately reduced. Adverse effects were observed in 5.5% of patients, including gastrointestinal in 3.8%. CONCLUSIONS: Sulodexide therapy was shown to reduce AER in patients with DN.