Design, synthesis, biological evaluation, and in silico studies of novel pyridopyridine derivatives as anticancer candidates targeting FMS kinase.

Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety.

Autophagy inhibition potentiates energy restriction-induced cell death in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) significantly contributes to cancer-related mortality due to the limited response of HCC to current anticancer therapies, thereby necessitating more effective treatment approaches. Energy restriction mimetic agents (ERMAs) have emerged as potential therapies in targeting the Warburg effect, a unique metabolic process in cancer cells. However, ERMAs exhibit limited efficacy when used as monotherapy.

Synthesis, biological evaluation, and stability studies of raloxifene mono- and bis-sulfamates as dual-targeting agents.

All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker.

Antimicrobial activity of nature-inspired molecules against multidrug-resistant bacteria.

Multidrug-resistant bacterial infections present a serious challenge to global health. In addition to the spread of antibiotic resistance, some bacteria can form persister cells which are tolerant to most antibiotics and can lead to treatment failure or relapse. In the present work, we report the discovery of a new class of small molecules with potent antimicrobial activity against Gram-positive bacteria and moderate activity against Gram-negative drug-resistant bacterial pathogens.

Evaluation of 2,3-dihydroimidazo[2,1-]oxazole and imidazo[2,1-]oxazole derivatives as chemotherapeutic agents.

Imidazo[2,1-]oxazole and 2,3-dihydroimidazo[2,1-]oxazole ring systems are commonly employed in therapeutically active molecules. In this article, the authors review the utilization of these core scaffolds as chemotherapeutic agents from 2018 to 2022. These scaffolds possess many important biological activities including antimicrobial and anticancer, among others.

The latest perspectives of small molecules FMS kinase inhibitors.

FMS kinase is a type III tyrosine kinase receptor that plays a central role in the pathophysiology and management of several diseases, including a range of cancer types, inflammatory disorders, neurodegenerative disorders, and bone disorders among others. In this review, the pathophysiological pathways of FMS kinase in different diseases and the recent developments of its monoclonal antibodies and inhibitors during the last five years are discussed. The biological and biochemical features of these inhibitors, including binding interactions, structure-activity relationships (SAR), selectivity, and potencies are discussed.

Design and synthesis of novel anti-urease imidazothiazole derivatives with promising antibacterial activity against Helicobacter pylori.

Urease enzyme is a known therapeutic drug target for treatment of Helicobacter pylori infection due to its role in settlement and growth in gastric mucosa. In this study, we designed a new series of sulfonates and sulfamates bearing imidazo[2,1-b]thiazole scaffold that exhibit a potent inhibitory activity of urease enzyme. The most potent compound 2c inhibited urease with an IC50 value of 2.

Complexity-to-Diversity and Pseudo-Natural Product Strategies as Powerful Platforms for Deciphering Next-Generation Therapeutics.

Stereochemical and skeletal complexity are particularly important vis-à-vis the cross-talks between a small molecule and a complementary active site of a biological target. This intricate harmony is known to increase selectivity, reduce toxicity, and increase the success rate in clinical trials. Therefore, the development of novel strategies for establishing underrepresented chemical space that is rich in stereochemical and skeletal diversity is an important milestone in a drug discovery campaign.

Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19.

The recent emergence of different SARS-CoV-2 variants creates an urgent need to develop more effective therapeutic agents to prevent COVID-19 outbreaks. Among SARS-CoV-2 essential proteases is papain-like protease (SARS-CoV-2 PLpro), which plays multiple roles in regulating SARS-CoV-2 viral spread and innate immunity such as deubiquitinating and deISG15ylating (interferon-induced gene 15) activities. Many studies are currently focused on targeting this protease to tackle SARS-CoV-2 infection.

Interaction of an anticancer benzopyrane derivative with DNA: Biophysical, biochemical, and molecular modeling studies.

Background: SIMR1281 is a potent anticancer lead candidate with multi- target activity against several proteins; however, its mechanism of action at the molecular level is not fully understood. Revealing the mechanism and the origin of multitarget activity is important for the rational identification and optimization of multitarget drugs.

Methods: We have used a variety of biophysical (circular dichroism, isothermal titration calorimetry, viscosity, and UV DNA melting), biochemical (topoisomerase I & II assays) and computational (molecular docking and MD simulations) methods to study the interaction of SIMR1281 with duplex DNA structures.

Divergent Protocol for the Synthesis of Isoquinolino[1,2-]quinazolinone and Isoquinolino[2,1-]quinazolinone Derivatives.

The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities.

Design and synthesis of new adamantyl derivatives as promising antiproliferative agents.

A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A).

Blue Light-Driven [4+2]-Cycloaddition: Diastereoselective Synthesis of Chromeno[4,3-]quinoline and Chromeno[4,3-][1,8]naphthyridine Scaffolds.

A one-pot, metal-free, light-driven [4+2]-cycloaddition reaction is described by accessing a diverse collection of chromeno[4,3-]quinoline and chromeno[4,3-][1,8]naphthyridine scaffolds in a diastereoselective manner. This process delivered stereoisomers, which were challenging to produce by an inverse-demand Diels-Alder reaction. The tetracyclic products were provided in good yields, promoted by rose bengal and blue light in a single operation.

Design, synthesis, and biological evaluation of a new series of pyrazole derivatives: Discovery of potent and selective JNK3 kinase inhibitors.

The design, synthesis, and biological activities of a new series of pyrazole derivatives are reported. The target compounds 1a-1w were initially investigated against NCI-60 cancer cell lines. Compounds 1f, 1h, 1k, and 1v exerted the highest anti-proliferative activity over the studied panel of cancer cell lines.

Progress in Gelatin as Biomaterial for Tissue Engineering.

Tissue engineering has become a medical alternative in this society with an ever-increasing lifespan. Advances in the areas of technology and biomaterials have facilitated the use of engineered constructs for medical issues. This review discusses on-going concerns and the latest developments in a widely employed biomaterial in the field of tissue engineering: gelatin.

Unveiling the mechanism of action of nature-inspired anti-cancer compounds using a multi-omics approach.

The 2020 global cancer registry has ranked breast cancer (BCa) as the most commonly diagnosed type of cancer and the most common cause of cancer-related deaths in women worldwide. Increasing resistance and significant side effects continue to limit the efficacy of anti-BCa drugs, hence the need to identify new drug targets and to develop novel compounds to overcome these limitations. Nature-inspired anti-cancer compounds are becoming increasingly popular since they often provide a relatively safe and effective alternative.

Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity.

This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity.

The 3D Bioprinted Scaffolds for Wound Healing.

Skin tissue engineering and regeneration aim at repairing defective skin injuries and progress in wound healing. Until now, even though several developments are made in this field, it is still challenging to face the complexity of the tissue with current methods of fabrication. In this review, short, state-of-the-art on developments made in skin tissue engineering using 3D bioprinting as a new tool are described.

Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Persisters.

The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant (MRSA). The compounds were efficiently synthesized in one-pot employing a cascade of Groebke-Blackburn-Bienaymé and aza-Michael addition reactions.

Metabolic conversion of β-pinene to β-ionone in rats.

Exposure to or ingestion of turpentine can alter the scent of urine, conferring it a flowery, violet-like scent. Turpentine's effect on urine was initially noticed after its use either as medicine or as a preservative in winemaking. Regardless of the source of exposure, the phenomenon requires metabolic conversion of turpentine component(s) to ionone, the molecule mainly responsible for the scent of violets.

Stereoselective Late-Stage Transformations of Indolo[2,3-]quinolizines Skeleta to Nature-Inspired Scaffolds.

The indolo[2,3-]quinolizines, canthines, and arborescidines natural products exhibit a wide range of bioactivities including anticancer, antiviral, antibacterial, and anti-inflammatory, among others. Therefore, the development of modular and efficient strategies to access the core scaffolds of these classes of natural products is a remarkable achievement. The Complexity-to-Diversity (CtD) strategy has become a powerful tool that transforms natural products into skeletal and stereochemical diversity.

Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment.

The main protease of SARS-CoV-2 virus, M, is an essential element for viral replication, and inhibitors targeting M are currently being investigated in many drug development programs as a possible treatment for COVID-19. An pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for M. These efforts identified a number of hits.

Current Status of Baricitinib as a Repurposed Therapy for COVID-19.

The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of preclinical and initial safety studies. BenevolentAI's large knowledge graph repository of structured medical information suggested baricitinib, a Janus-associated kinase inhibitor, as a potential repurposed medicine with a dual mechanism; hindering SARS-CoV2 entry and combatting the cytokine storm; the leading cause of mortality in COVID-19.