Fishing antioxidant 4-hydroxycoumarin derivatives: synthesis, characterization, and in vitro assessments.

Coumarins represent a diverse class of natural compounds whose importance in pharmaceutical and agri-food sectors has motivated multiple novel synthetic derivatives with broad applicability. The phenolic moiety in 4-hydroxycoumarins underscores their potential to modulate the equilibrium between free radicals and antioxidant species within biological systems. The aim of this work was to assess the antioxidant activity of 18 4-hydroxycoumarin coumarin derivatives, six of which are commercially available and the other 12 were synthesized and chemically characterized and described herein. The 4-hydroxycoumarins were prepared by a two steps synthetic strategy with satisfactory yields. Their antioxidant potential was evaluated through three in vitro methods, two free radical-scavenging assays (DPPH• and ABTS•+) and a metal chelating activity assay. Six synthetic coumarins (4a, 4g, 4h, 4i, 4k, 4l) had a scavenging capacity of DPPH• higher than butylated hydroxytoluene (BHT) (IC50 = 0.58 mmol/L) and compound 4a (4-hydroxy-6-methoxy-2 H-chromen-2-one) with an IC50 = 0.05 mmol/L outperformed both BHT and ascorbic acid (IC50 = 0.06 mmol/L). Nine hydroxycoumarins had a scavenging capacity against ABTS•+ greater (C3, 4a, 4c) or comparable (C1, C2, C4, C6, 4g, 4l) to Trolox (IC50 = 34.34 µmol/L). Meanwhile, the set had a modest ferrous chelation capacity, but most of them (C2, C5, C6, 4a, 4b, 4h, 4i, 4j, 4k, 4l) reached up to more than 20% chelating ability percentage. Collectively, this research work provides valuable structural insights that may determine the scavenging and metal chelating activity of 4-hydroxycoumarins. Notably, substitutions at the C6 position appeared to enhance scavenging potential, while the introduction of electron-withdrawing groups showed promise in augmenting chelation efficiency.

The association between angiotensin receptor blockers and lung, bladder, and colon cancer development: A 10-year multicentric retrospective Lebanese study.

Cardiovascular diseases (CVD) are the leading cause of death globally, followed by cancer. Angiotensin II contributes greatly to CVD pathogenesis, and Angiotensin II receptor blockers (ARBs) constitute a mainstay in hypertension and CVD management. However, the relationship between ARBs and cancer initiation is controversial, with no clear data in Lebanon. Therefore, our study aimed to determine the association between ARBs intake and lung, bladder, and colorectal cancers development in the Lebanese population. A retrospective study was conducted on 709 subjects divided into 2 main groups: Control (subjects without cancer; n = 177), and Cases (patients with cancer (n = 532): lung, bladder, or colorectal), taking ARBs (n = 236, (n = 121 in control and n = 115 in cases)) or not (n = 473). Collected information included the patients demographics, comorbidities, cancer's risk factors, and ARBs dose and duration intake. Bivariate, multivariate, and binary logistic analyses were enrolled. ARBs use was significantly protective (P value = 0.000) against overall cancer development (odds ratio [OR] = 0.127) and against each, lung (OR < 1), bladder (OR < 1), and colorectal cancers (OR < 1). A duration-response relationship was established. This protective effect and the time-dependent relationship remained unchanged after omitting the most relevant risk factors. In summary, a significant overall protective effect of ARBs against lung, bladder and colorectal cancers was found. This beneficial response was time-dependent. These results can guide patients on treatment options and clinicians for informed decision-making.

Statins, commonly coprescribed drugs, and concomitant risk factors: A protective, neutral, or harmful association with common cancer types development: A 10-year multicentric retrospective lebanese study.

Elevated blood levels of low-density lipoprotein cholesterol are a major cardiovascular risk factor, and cholesterol-lowering drugs are among the most prescribed drugs worldwide. Cancer is the second leading cause of death after cardiovascular diseases. The relationship between cancer development and statins intake is controversial, and there are no clear studies in Lebanon and the Middle East concerning this topic. Hence, our study aimed to search for any possible association of statin intake as well as other medications (proton pump inhibitors [PPI], metformin, Aspirin, Angiotensin-Converting Enzyme inhibitors, and fenofibrate) with lung, colorectal cancer (CRC), and bladder cancer development in the Lebanese population. A retrospective study was performed on 709 subjects divided into 2 main groups: control (no cancer ± statin intake), and cases (either lung, or colorectal, or bladder cancer ± statin intake). Collected data included the age and gender of the patient, socioeconomic status, presence of cardiovascular disease and comorbidities, cancer risk factors, and the intake type, dose, and duration of statins. Bivariate, multivariate, and binary logistic analyses were enrolled. Out of 709 participants, 63.2% were males and 75% were cancer-positive (24.1%: lung cancer, 26.7%: CRC, 24.1%: bladder cancer). The overall intake of statins was not shown to significantly affect cancer development. However, a duration-response relationship was established between Simvastatin and lung cancer (odds ratio [OR]=1.208) as well as bladder cancer (OR=1.189). No significant association was found between each statin and CRC. Although PPIs intake was associated with a possibly harmful effect on lung cancer development (OR=3.42), it revealed a protective association with CRC development (OR=0.38). Other risk factors such as smoking and age were strongly associated (harmful) with lung and bladder cancer development. Physical inactivity and a family history of CRC were each associated with a harmful effect on CRC development. A harmful association with the development of lung and bladder cancer was found with the increasing duration of intake of Simvastatin. Other drugs such as PPIs and specific risk factors were also associated negatively or positively with the development of these 3 cancers. These findings should be validated by further investigations to guide clinicians on optimal treatment options for their patients.

Coumarins derivatives and inflammation: Review of their effects on the inflammatory signaling pathways.

Natural and synthetic coumarins have been extensively described in the literature as effective drugs with several pharmacological activities. Many valuable publications have shown the anti-inflammatory potential of these compounds suggesting that coumarins could be an interesting scaffold for developing new therapeutic anti-inflammatory agents. However, despite the continuous efforts of research in this field, no major breakthrough was yet achieved and only a few coumarin-like drugs are commercially available. In the present article, we reviewed the most relevant studies conducted in the last two decades (2000-2021) and presenting evidence for the anti-inflammatory mechanisms of coumarins. The review provides a comprehensive survey of scientific research revealing through multiple in vitro and in vivo models the effect of natural and synthetic coumarins on components of the Toll-like receptors (TLR), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Inflammasomes, mitogen-activated protein kinase (MAPK), nuclear factor- κ-light-chain-enhancer of activated B cells (NF- κB) and transforming growth factor-ß/small mothers against decapentaplegic (TGF-ß/SMAD) pathways.

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes.

The discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

Novel and Selective TLR7 Antagonists among the Imidazo[1,2-a]pyrazines, Imidazo[1,5-a]quinoxalines, and Pyrazolo[1,5-a]quinoxalines Series.

The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine adjuvants. However, the chronic immune activation by excessive TLR stimulation is a hallmark of several clinically important infectious and autoimmune diseases, which warrants the search for TLR antagonists. In this study, we have synthesized and characterized a variety of compounds belonging to three heterocyclic chemical series: imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline. These compounds have been tested for their TLR7 or TLR8 agonistic and antagonistic activities. Several of them are shown to be selective TLR7 antagonists without any TLR7 or TLR8 agonistic activity. The selectivity was confirmed by a comparative ligand-docking study in TLR7 antagonist pocket. Two compounds of the pyrazolo[1,5-a]quinoxaline series (10a and 10b) are potent selective TLR7 antagonists and may be considered as promising starting points for the development of new therapeutic agents.

Prevalence and Distribution of Oral Mucosal Lesions by Sex and Age Categories: A Retrospective Study of Patients Attending Lebanese School of Dentistry.

BACKGROUND: Prevalence and distribution of oral mucosal lesions in a sample of Lebanese population attending the School of Dentistry of Lebanese University is necessary to evaluate their oral health situation. OBJECTIVES: The aim of the present study was to determine the prevalence and distribution of oral mucosal lesions of patients attending the School of Dentistry. METHODS: A descriptive study was carried out by retrospectively examining a total of 231 medical and clinical examination record files of patients, attending the School of Dentistry Lebanese University for multidisciplinary dental treatments. 178 medical records were retained. Each medical and clinical examination record was done by an undergraduate student and then evaluated by a doctor. The record file included a civil status, chief complaint, medical history, and extraoral and intraoral clinical examination during the period between October 2014 and May 2015. Exclusion criteria were lack of written information in their medical and clinical examination record and being nonevaluated by a doctor. Data regarding age, gender, socioeconomic status, chief complaint, systemic diseases, and drugs intake were collected by using a questionnaire while the type of extraoral and oral mucosal lesions by clinical examination. RESULTS: The sample consisted of 102 (57.3%) females and 76 (42.7%) males. The age ranged from 10 to 92 years with a mean age of 40.1 years. Among these subjects, 110 (61.8%) presented with one or more lesions. All patients were Lebanese. The most common lesion diagnosed was coated/hairy tongue affecting 17.4% of the subjects, followed by melanotic macule (11.2%), gingivitis (9.6), linea alba (6.2%), tongue depapillation (5.1), leukoplakia (5.1), traumatic fibroma (4.5), frictional keratosis (3.9%), fissured tongue (3.9%), hemangiomas (3.9%), Fordyce granules (3.9%), dry mucosa (3.4), angular cheilitis (2.2), gingival hyperplasia (2.2), and crenulated tongue (1.7%). Overall, the prevalence of oral mucosal lesions did not significantly differ between sex and age groups. CONCLUSIONS: The high prevalence of oral mucosal lesions necessitates adequate awareness and management of these lesions in the general population. Dental clinicians should be knowledgeable and familiar with the etiopathogenesis, clinical presentation, diagnosis, and management of these lesions.

Imidazo[1,2-a]pyrazine, Imidazo[1,5-a]quinoxaline and Pyrazolo[1,5-a]quinoxaline derivatives as IKK1 and IKK2 inhibitors.

The transcription nuclear factor NF-κB plays a pivotal role in chronic and acute inflammatory diseases. Among the several and diverse strategies for inhibiting NF-κB, one of the most effective approach considered by the pharmaceutical industry seems to be offered by the development of IKK inhibitors. In a former study, two potential IKK2 inhibitors have been highlighted among a series of imidazo[1,2-a]quinoxaline derivatives. In order to enhance this activity, we present herein the synthesis of twenty-one new compounds based on the imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline or pyrazolo[1,5-a]quinoxaline structures. Their potential to inhibit IKK1 and IKK2 activities is also tested.

New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships.

Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122µM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.

Histidine based adsorbents for selective removal of monoclonal immunoglobulin IgM antibodies from Waldenstrom's macroglobulinemia patient sera: a preliminary study.

Waldenstrom's macroglobulinemia (WM) is considered by the Revised European American Lymphoma (REAL) and World Health Organization (WHO) as a clinical lympho plasmacytic syndrome associated with high monoclonal (IgM) secretion. The hyper viscosity syndrome is associated with several clinical disorders of monoclonal IgM. Patients with clinical symptoms of hyper viscosity should be treated with plasma pheresis, which is limited by its non-selective removal of all plasma components. These limitations have steered efforts to find a more specific removal according to clinical needs and avoiding plasma components replacement. Removal by specific adsorption is the most powerful selective apheresis technique. The active adsorbed ligand is covalently bound to an insoluble matrix through which plasma is passed. Amino acids have been introduced as ligands in clinical apheresis for the removal of auto antibodies associated with autoimmune diseases. The present preliminary study describes the binding of monoclonal IgM antibodies from sera of patients with WM, on histidine immobilized to activated sepharose. The advantages of efficient binding and elution, suggest histidine adsorbents as prospective clinical means suitable for the removal of monoclonal IgM from sera of patients diagnosed with WM. The advantages of efficient adsorption and elution, non toxicity of histidine, good selectivity, good stability, as well as their low cost strongly suggest histidine adsorbents as prospective clinical means suitable for the removal of monoclonal IgM from sera of patients diagnosed with WM.

Synthesis and antiproliferative activity of oxazinocarbazole and N,N-bis(carbazolylmethyl)amine derivatives.

The synthesis, structure elucidation and antitumoral activity of novel heterocyclic compounds containing a carbazole nucleus are reported. Oxazinocarbazoles were synthesized by application of the Mannich reaction to the corresponding hydroxylated derivatives leading to 41 new molecules. Their cytotoxic activity was evaluated against various human tumor cell lines including three leukemic cell lines: CEM and Jurkat (type T), Raji (type B); breast cancer cell line (MCF-7); colorectal cancer cell line (Caco-2). A primary screening at 100 microM allowed the selection of the 10 most active compounds, which showed an antiproliferative activity on all the cell lines. A dose-effect study between 12.5 and 100 microM sorted two compounds with a significant activity: 5t and 7e against leukemic cell lines CEM, Jurkat and Raji with IC50 values around 12 microM.

[Setup of a national system of adverse drug reaction reporting in Lebanon: results of the first year of activity]. / Mise en place d'un systemè national de recueil des effets indésirables des médicaments au Liban: résultats de la première année d'activité.

OBJECTIVE: The aim of this publication is to present the results of the first year of activity of the national adverse drug reactions (ADR) reporting system in Lebanon. METHODS: We started our survey with 3 teaching hospitals (more than 160 beds/hospital). Pharmacy students were responsible for collecting and investigating ADRs reported by physicians. RESULTS: After 7 months, 40 cases of suspected ADRs were reported, of which the majority (32 cases) had a causality score of "probable" according to the French method of causality assessment. Skin and allergic reactions occurred in the largest proportion of the ADRs reported (46%). The most common drugs involved in the ADRs were antimicrobial agents (43%) followed by anticonvulsant and anticoagulant drugs (12% each). CONCLUSION: Our objectives are to extend the reporting system in other hospitals throughout Lebanon.