Coumarin structure as a lead scaffold for antibacterial agents - molecular docking

Coumarins owe their class name to “Coumarou”, the vernacular name of the tonka bean (Dipteryx odorata Willd, Fabaceae), from which coumarin was isolated in 1820. Many molecules based on the coumarin structure have been synthesized utilizing innovative synthetic techniques. Various synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins and coumarinsulfamates which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, as stimulants for central nervous system, antiinflammatory therapy, as anti-coagulants, etc. One of important pharmacological activity of coumarin molecules is their potential as antibacterial agents since they show inhibitory activity toward isoleucyl-transfer RNA (tRNA) synthetase. In the presented research molecular docking studies of selected coumarin compounds inside isoleucyltransfer RNA (tRNA) synthetase active site were performed. Molecular docking scores of all studied compounds were obtained through score functions. Presented results indicate that from all studied coumarin compounds the strongest interactions with studied enzyme has 7,8-dihydroxy-4-phenyl coumarin followed by 5,7-dihydroxy-4-phenyl coumarin. Presented results are in accordance with in vitro obtained results for their antibacterial activity. Presented findings suggest that 4-phenyl hydroxycoumarins may be considered as good molecular templates for potential antibacterial agents and can be used for further chemical modifications for improving their antibacterial activity

Monte Carlo QSAR models for predicting organophosphate inhibition of acetycholinesterase

<div><p>A series of 278 organophosphate compounds acting as acetylcholinesterase inhibitors has been studied. The Monte Carlo method was used as a tool for building up one-variable quantitative structure–activity relationship (QSAR) models for acetylcholinesterase inhibition activity based on the principle that the target endpoint is treated as a random event. As an activity, bimolecular rate constants were used. The QSAR models were based on optimal descriptors obtained from Simplified Molecular Input-Line Entry System (SMILES) used for the representation of molecular structure. Two modelling approaches were examined: (1) ‘classic’ training-test system where the QSAR model was built with one random split into a training, test and validation set; and (2) the correlation balance based QSAR models were built with two random splits into a sub-training, calibration, test and validation set. The DModX method was used for defining the applicability domain. The obtained results suggest that studied activity can be determined with the application of QSAR models calculated with the Monte Carlo method since the statistical quality of all build models was very good. Finally, structural indicators for the increase and the decrease of the bimolecular rate constant are defined. The possibility of using these results for the computer-aided design of new organophosphate compounds is presented.</p></div

Postoperative and Pathological Outcomes of CROSS and FLOT as Neoadjuvant Therapy for Esophageal and Junctional Adenocarcinoma: An International Cohort Study From the Oesophagogastric Anastomosis Audit (OGAA)

Objective: This study aimed to compare the postoperative and pathological outcomes between carboplatin, paclitaxel, radiotherapy (CROSS) and 5-FU, leucovorine, oxaliplatin and docetaxel (FLOT) in esophageal adenocarcinoma (EAC) patients from an international, multicenter cohort. Summary of Background Data: Ongoing debate exists around optimum approach to locally advanced EAC, with proponents for perioperative chemotherapy, such as FLOT, or multimodal therapy, in particular the CROSS regimen. Methods: Patients undergoing CROSS (n = 350) and FLOT (n = 368), followed by curative esophagectomy for EAC were identified from the Oesophagogastric Anastomosis Audit. Results: The 90-day mortality was higher after CROSS than FLOT (5% vs 1%, P = 0.005), even on adjusted analyses [odds ratio (OR): 3.97, confidence interval (CI)95%: 1.34-13.67]. Postoperative mortality in CROSS were related to higher pulmonary (74% vs 60%) and cardiac complications (42% vs 20%) compared to FLOT. CROSS was associated with higher pathologic complete response (pCR) rates (18% vs 10%, P = 0.004) and margin-negative resections (93% vs 76%, P < 0.001) compared with FLOT. On adjusted analyses, CROSS was associated with higher pCR rates (OR: 2.05, CI95%: 1.26-3.34) and margin-negative resections (OR: 4.55, CI95%: 2.70-7.69) compared to FLOT. Conclusions: This study provides real-world data CROSS was associated with higher 90-day mortality than FLOT, related to cardio-pulmonary complications with CROSS. These warrant a further review into causes and mechanisms in selected patients, and at minimum suggest the need for strict radiation therapy quality assurance. Research into impact of higher pCR rates and R0 resections with CROSS compared to FLOT on long-term survival is needed