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

Biological Activity of Quinazolinones

The chemical structure of quinazolinones includes benzene ring fused with 2-pyrimidinone (1), 4-pyrimidinone (2) or 2,4-pyrimidinedione (3) ring, and are named as quinazolin-2(1H)-one, quinazolin-4(3H)-one or quinazolin-2,4(1H, 3H)-one, respectively. The chemical structure of quinazolinones constitutes a crucial scaffold of natural and synthetic compounds with various therapeutic and biological activities. Quinazolinones are first synthesized by Stefan Niementowski (1866–1925) and named after Niementowski quinazolinone synthesis. Quinazolinones have strongly attracted the interest of medicinal chemist as they constitute a large class of compounds that exhibited broad spectrum of biological activities including antimicrobial, antimalarial, anticonvulsant, anticancer, antileishmanial, anti-inflammatory, etc. This chapter provides a brief overview on the recent advances on chemical and pharmacological aspects of quinazolinone derivatives published in the last decade

Pharmacophore Elucidation and Molecular Docking Studies on 5-Phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic Acid Derivatives as COX-2 Inhibitors

A set of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives (16–32) showing anti-inflammatory activity was analyzed using a three-dimensional qualitative structure-selectivity relationship (3D QSSR) method. The CatalystHipHop approach was used to generate a pharmacophore model for cyclooxygenase-2 (COX-2) inhibitors based on a training set of 15 active inhibitors (1–15). The degree of fitting of the test set compounds (16–32) to the generated hypothetical model revealed a qualitative measure of the more or less selective COX-2 inhibition of these compounds. The results indicate that most derivatives (16, 18, 20–25, and 30–32) are able to effectively satisfy the proposed pharmacophore geometry using energy accessible conformers (Econf < 20 kcal/mol). In addition, the triazole derivatives (16–32) were docked into COX-1 and COX-2 X-ray structures, using the program GOLD. Based on the docking results it is suggested that several of these novel triazole derivatives are active COX inhibitors with a significant preference for COX-2. In principle, this work presents an interesting, comprehensive approach to theoretically predict the mode of action of compounds that showed anti-inflammatory activity in an in vivo model

Molecular scaffold and biological activities of anti- Alzheimer agents

Alzheimer’s disease (AD) is an age-associated and neurodegenerative illness which results in progressive dementia and severe cognitive malfunctions. The pathogenesis of AD is affected by some factors such as accumulation of β-amyloid, aggregation of tau protein, cholinergic insufficiency, neuroinflammation, oxidative stress and apoptosis. Factors such as gene mutation, as well as environmental, psychical and other co-existing diseases influence the pathogenesis of AD to varying extents. While there are no available drugs for arresting AD-associated neurodegeneration, the characteristics that result from AD treatment are considered as indexes of symptomatic cure. Several medications with varied scaffolds have been used for the treatment of many cognitive syndromes, including AD. These medications act as anti-inflammatory and antioxidant agents, and as inhibitors of cholinesterase and β-secretase. Moreover, these drugs suppress the accumulation of β-amyloid and its fibril. This review is an update and compilation of various scaffolds of anti-AD medications used to ameliorate the deleterious effects of the disease, based on their pharmacologic characteristics

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

Call for emergency action to restore dietary diversity and protect global food systems in times of COVID-19 and beyond: Results from a cross-sectional study in 38 countries

Background: The COVID-19 pandemic has revealed the fragility of the global food system, sending shockwaves across countries\u27 societies and economy. This has presented formidable challenges to sustaining a healthy and resilient lifestyle. The objective of this study is to examine the food consumption patterns and assess diet diversity indicators, primarily focusing on the food consumption score (FCS), among households in 38 countries both before and during the first wave of the COVID-19 pandemic. Methods: A cross-sectional study with 37 207 participants (mean age: 36.70 ± 14.79, with 77 % women) was conducted in 38 countries through an online survey administered between April and June 2020. The study utilized a pre-tested food frequency questionnaire to explore food consumption patterns both before and during the COVID-19 periods. Additionally, the study computed Food Consumption Score (FCS) as a proxy indicator for assessing the dietary diversity of households. Findings: This quantification of global, regional and national dietary diversity across 38 countries showed an increment in the consumption of all food groups but a drop in the intake of vegetables and in the dietary diversity. The household\u27s food consumption scores indicating dietary diversity varied across regions. It decreased in the Middle East and North Africa (MENA) countries, including Lebanon (p \u3c 0.001) and increased in the Gulf Cooperation Council countries including Bahrain (p = 0.003), Egypt (p \u3c 0.001) and United Arab Emirates (p = 0.013). A decline in the household\u27s dietary diversity was observed in Australia (p \u3c 0.001), in South Africa including Uganda (p \u3c 0.001), in Europe including Belgium (p \u3c 0.001), Denmark (p = 0.002), Finland (p \u3c 0.001) and Netherland (p = 0.027) and in South America including Ecuador (p \u3c 0.001), Brazil (p \u3c 0.001), Mexico (p \u3c 0.0001) and Peru (p \u3c 0.001). Middle and older ages [OR = 1.2; 95 % CI = [1.125–1.426] [OR = 2.5; 95 % CI = [1.951–3.064], being a woman [OR = 1.2; 95 % CI = [1.117–1.367], having a high education (p \u3c 0.001), and showing amelioration in food-related behaviors [OR = 1.4; 95 % CI = [1.292–1.709] were all linked to having a higher dietary diversity. Conclusion: The minor to moderate changes in food consumption patterns observed across the 38 countries within relatively short time frames could become lasting, leading to a significant and prolonged reduction in dietary diversity, as demonstrated by our findings

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)

Design and synthesis of multi-functional small-molecule based inhibitors of amyloid-β aggregation: Molecular modeling and in vitro evaluation.

Amyloid-β1-42 (Aβ42) peptide aggregate formation in the brain plays a crucial role in the onset and progression of Alzheimer's disease. According to published research, the Aβ monomer's amino acid residues KLVFF (16-20) self-associate to create antiparallel β-sheet fibrils. Small compounds can prevent self-assembly and destroy Aβ fibrils by attaching to the Aβ16-20 regions of Aβ42. To enhance biological characteristics and binding affinity to the amyloid beta peptide, β-sheet breaker small molecules can be developed and modified with various scaffolds. In the current study, a novel series of 2,3-disubstitutedbenzofuran derivatives was designed and created by fusing the benzofuran core of a known iron chelator, neuroprotective, and neurorestorative agent, like VK-28, with a motif found in the structure of a known muscarinic inhibitor and amyloid binding agent, like SKF-64346. Measurements of the binding affinity and in vitro aggregation inhibition of the Aβ42 peptide were made using the thioflavin T (ThT) test. Using AutoDock 4.2 software, molecular docking studies of the synthesized compounds were performed on the monomer and fibril structures of amyloid beta peptide. The compounds 8a-8g exhibited strong binding energy and affinity to Aβ fibrils as well as a 50%-67% reduction of the growth of Aβ aggregation. Finally, the positive traits of our recently synthesized compounds make them excellent candidates for additional in vivo testing as a "β-sheet breaking agent.