In silico studies on novel inhibitors of MERS-CoV: Structure-based pharmacophore modeling, database screening and molecular docking

Purpose: To search for novel scaffolds as potential inhibitors of 3CLpro protease enzyme and as antiviral drugs.Methods: NCI database was screened using structure-based  pharmacophore modeling, database screening and molecular docking. Also, Lipininski’s rule of 5 was applied in order to test the druglikenessof the retrieved compound. Pharmacophore modelling and subsequent post-docking analyses were used for comparison of the binding mode of the retrieved hits with that of the x-ray inhibitor, R30, against MERS-CoV 3CLpro enzyme.Results: Five compounds were identified as potential agents for the  treatment of corona virus, MERSCoV, which showed similar binding to MERS-CoV 3CLpro like that of the x-ray inhibitor, R30. As protease enzyme plays an indispensable role during virus life cycle, CoV 3CLpro has been reported as a highly validated drug target and it is considered viable for the design of broad spectrum inhibitors. The selected five hit compounds bind to MERS-CoV 3CLpro in a manner similar to that of the x-ray inhibitor, R30, and showed pharmacophore-fit and docking score values higher than those of R30, MERS-CoV 3CLpro-inhibitor.Conclusion: The retrieved five hits are proposed as new scaffolds for further evaluation and optimization of their activity against MERS-CoV.Keywords: MERS-CoV pharmacophore, Molecular docking, Protease enzyme, X-ray inhibito

Novel ethyl 1,5-disubstituted-1H-pyrazole-3-carboxylates as a new class of antimicrobial agents

A series of pyrazole derivatives 9-22 were designed and synthesized. All the newly synthesized compounds were assayed for their antimicrobial activity against the Gram-positive bacteria Staphyllococcus aureus and Bacillius subtilis and the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, in addition to the fungi organisms, Candida albicans, C. parapsilosis and C. tropicalis. Ethyl 5-(2,5-dimethylthiophen-3-yl)-1-phenyl-1H-pyrazole-3-carboxylate (21) (MICE.coli =0.038 µmol mL–1, MICP. aerug = 0.067 µmol mL–1) is nearly as active as ampicillin (MIC = 0.033 and 0.067 µmol mL–1, respectively). Ethyl 5-(4-bromo-2-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (16) (MIC = 0.015 µmol mL–1) is more active than fluconazole (0.020 µmol mL–1) as a reference drug against C. parapsilosis

Design and Synthesis of New Cholesterol-Conjugated 5-Fluorouracil: A Novel Potential Delivery System for Cancer Treatment

Cholesterol-conjugated 5-fluorouracil prodrugs were designed to be carried in vivo via low density lipoproteins (LDL) and subsequently undergo LDL-receptor-mediated internalisation into cancer cells. In vivo anti-cancer evaluation was performed using 5-fluorouracil-cholesterol conjugate in a mouse model. The obtained prodrugs were more potent than 5-fluorouracil control drug at the same 5-fluorouracil content (3 mg·kg−1)

Novel Ethyl 1,5-Disubstituted-1H-Pyrazole-3-Carboxylates as a New Class of Antimicrobial Agents

A series of pyrazole derivatives 9-22 were designed and synthesized. All the newly synthesized compounds were assayed for their antimicrobial activity against the Grampositive bacteria Staphyllococcus aureus and Bacillius subtilis and the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, in addition to the fungi organisms, Candida albicans, C. parapsilosis and C. tropicalis. Ethyl 5-(2,5-dimethylthiophen- 3-yl)-1-phenyl-1H-pyrazole-3-carboxylate (21) (MICE.coli = 0.038 μmol mL-1, MICP. aerug. = 0.067 μmol mL-1) is nearly as active as ampicillin (MIC = 0.033 and 0.067 μmol mL-1), respectively. Ethyl 5-(4-bromo-2-chlorophenyl)- 1-phenyl-1H-pyrazole-3-carboxylate (16) (MIC = 0.015 μmol mL-1) is more active than fluconazole (0.020 μmol mL-1) as a reference drug against C. parapsilosis

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AimThe SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery.MethodsThis was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin.ResultsOverall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P ConclusionOne in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease