Characterizing Cardiotoxicity of FDA-Approved Soft Tissue Sarcoma Targeted Therapies and Immune Checkpoint Inhibitors: A Systematic Review.

: Soft tissue sarcomas (STS) are aggressive cancers that show increasing response to novel targeted-therapies and immune-checkpoint-inhibitors. Despite anecdotal reports of cardiovascular adverse events (AEs) and major adverse cardiovascular events (MACE) potentially hindering their utility, the true cardiotoxic profile of these novel-therapies in STS has been largely understudied. : We assessed the incidence and severity of AEs and MACE of contemporary FDA-approved targeted and immune-based therapies for STS, using data from landmark clinical trials supporting FDA-approval.

HPO promoted reactions of thioamides with 2-substituted benzyl alcohols.

In this study, we have investigated the reactivity of thioamides with alcohols by utilizing HPO as a low-toxicity, cost-effective Brønsted acid catalyst. This report includes a methodology for the synthesis of thioesters from thioamides and 2-hydroxyaryl alcohols. Thioesters are emerging as a notable class of organic molecules due to their biological relevance, extensive use in drug discovery, and industrial applications.

Regioselective Ring Opening of Aziridines by Oximes via C-C Bond Cleavage: Access to a Library of Oxime-Ethers.

A series of sulfonamido-substituted oxime-ethers have been synthesized by the reaction of donor-acceptor aziridines with aldo- and keto-oximes through C-C bond cleavage. Nucleophilic attack by an oxime hydroxyl group on the -generated azomethine ylide rather than the routine cycloaddition reaction draws the novelty of the developed methodology. Selective protection of the oxime hydroxyl group is observed in the presence of phenolic -OH, which made the protocol enriched.

Pharmacological Evaluation of Bakuchiol From Psoralea corylifolia L. as Potent Antimicrobial Agent Against Staphylococcus aureus.

The surge in multidrug resistance in Staphylococcus aureus is the pressing need to identify novel alternatives to combat antimicrobial resistance effectively. Bakuchiol is a bioactive prenylated phenolic meroterpene largely abundant in the seeds of Psoralea corylifolia. In this study, we present the biological assessment of bakuchiol derived from P.

Advancements and challenges in tuberculosis drug discovery: A comprehensive overview.

Tuberculosis continues to pose a health challenge causing the loss of millions of lives despite the existence of multiple drugs, for treatment. The emergence of drug-resistant strains has made the situation more complex making it increasingly difficult to fight against this disease. This review outlines the challenges associated with TB drug discovery, the nature of Mycobacterium tuberculosis shedding light on the mechanisms that lead to treatment failure and antibiotic resistance.

Solvent- and Catalyst-Controlled Regioselective - and -Alkylation of 2-Pyridones by 2-Azirines.

The synthesis of -substituted 2-hydroxypyridines and -substituted 2-pyridones, crucial for many bioactive compounds and drugs, faces challenges due to the tautomeric nature of 2-pyridones, which complicates selective alkylation. Here we developed an efficient method for regioselective - and -alkylation of 2-pyridones using Bro̷nsted acid-catalyzed ring opening of 2-azirines. The process involves triflic acid for -alkylation and -toluenesulfonic acid for alkylation, achieving high yields under optimized conditions.

Design, Synthesis, Evaluation of Antitubercular Activity and Insilco Studies of Novel 1,5-Naphthyridin-2(1H)-One Pendent 1,2,3-Triazoles.

A library of 1,5-Naphthyridin-2(1H)-one based 1,2,3-triazole analogues (11a-q) were synthesized via series of reactions such as protection, oxidation, cyclization and click chemistry. The new molecules were tested for their antitubercular activity against M. tuberculosis mc6230 and determined the minimum inhibitory concentration (MIC) employing Rifampicin as reference.

Development and Evaluation of Bis-benzothiazoles as a New Class of Benzothiazoles Targeting DprE1 as Antitubercular Agents.

Benzothiazole-bearing compounds have emerged as potential noncovalent DprE1 (decaprenylphosphoryl-β-d-ribose-2'-epimerase) inhibitors active against . Based on structure-based virtual screening (PDB ID: 4KW5), a focused library of thirty-one skeletally diverse benzothiazole amides was prepared, and the compounds were assessed for their antitubercular activity against H37Ra. Most potent compounds and were further evaluated against the H37Rv strain by the microdilution assay method.

Bi(III)-Catalyzed Michael Addition of Tautomerizable Heterocycles with α,β-Unsaturated Carbonyl Compounds: Regioselective Construction of C-N Bonds.

A Bi(III)-catalyzed synthetic strategy for regioselective construction of C-N bonds via a simple Michael addition reaction is reported. A wide range of tautomerizable heterocycles such as benzoxazolones, benzothiazolones, benzimidazolinones, indolinones, and 2-pyridones along with α,β-unsaturated carbonyls (ketones and esters) are employed to create a library of corresponding -alkylated derivatives exclusively. High regioselectivity, high atom economy, and the participation of a range of tautomerizable heterocycles highlight the uniqueness and generality of the developed methodology.

Regioselective Brønsted acid catalyzed ring opening of aziridines by phenols and thiophenols; a gateway to access functionalized indolines, indoles, benzothiazines, dihydrobenzo-thiazines, benzo-oxazines and benzochromenes.

Brønsted acid catalyzed regioselective ring opening of aziridines by phenols and thiophenols have been reported. Involvement of a series of aziridines with a range of phenols and thiophenols offer the generality of the reported protocol. Completion of the reaction at room temperature within very short time brings the uniqueness of the developed technique.

Brønsted acid-catalyzed regioselective ring opening of 2-azirines by 2-mercaptopyridines and related heterocycles; one pot access to imidazo[1,2-]pyridines and imidazo[2,1-]thiazoles.

A catalytic and versatile synthetic method for the synthesis of imidazo[1,2-]pyridines has been developed. Brønsted acid-catalysis plays a major role in the regioselective ring opening of 2-azirines. Nucleophilic attack the -centre of mercaptopyridines and their analogues, followed by cyclisation by cleaving the C-S bond, allowed a library of imidazo[1,2-]pyridines and related heterocycles to be built.

Applications of Inorganic Nanomaterials against Tuberculosis: A Comprehensive Review.

Tuberculosis (TB) continues to pose a significant global health threat, with millions of new infections recorded annually. Current treatment strategies, such as Directly Observed Treatment (DOT), face challenges, including patient non-compliance and the emergence of drug-resistant TB strains. In response to these obstacles, innovative approaches utilizing inorganic/metallic nanomaterials have been developed to enhance drug delivery to target alveolar macrophages, where Mycobacterium tuberculosis resides.

Cytochrome oxidase: an emerging anti-tubercular drug target.

Cytochrome (cyt-) oxidase, one of the two terminal oxidases in the () oxidative phosphorylation pathway, plays an indispensable role in maintaining the functionality of the metabolic pathway under stressful conditions. However, the absence of this oxidase in eukaryotic cells allows researchers to select it as a potential drug target for the synthesis of anti-tubercular (anti-TB) molecules. Cyt- inhibitors have often been combined with cytochrome / super-complex inhibitors in anti-TB drug regimens to achieve a desired bactericidal response.

Cell Type-Specific Extracellular Vesicles and Their Impact on Health and Disease.

Extracellular vesicles (EVs), a diverse group of cell-derived exocytosed particles, are pivotal in mediating intercellular communication due to their ability to selectively transfer biomolecules to specific cell types. EVs, composed of proteins, nucleic acids, and lipids, are taken up by cells to affect a variety of signaling cascades. Research in the field has primarily focused on stem cell-derived EVs, with a particular focus on mesenchymal stem cells, for their potential therapeutic benefits.

Methyltrifluoromethanesulfonate Catalyst in Direct Nucleophilic Substitution of Alcohols; One-Pot Synthesis of 4-Chromene Derivatives.

The catalytic activity of methyltrifluoromethanesulfonate (MeOTf) has been explored toward direct nucleophilic substitution of the hydroxyl group of nonmanipulated alcohols such as benzylic, allylic, propargylic, and tertiary alcohols with a wide range of uncharged nucleophiles such as 1,3-dicarbonyl compounds, amides, alkynes, and indoles to generate functionalized 1,3-dicarbonyl compounds, amides, alkynes, and indoles, respectively. Thus, the present protocol defines an alternate pathway to construct new C-C, C-N, and C-O bonds with the formation of water as the byproduct under mild conditions without any acids or metals. A completely different mechanism was established through several control experiments to explain the reaction methodology.

Regioselective Transition Metal-Free Catalytic Ring Opening of 2-Azirines by Phenols and Naphthols; One-Pot Access to Benzo- and Naphthofurans.

Benzofuran and naphthofuran derivatives are synthesized from readily available phenols and naphthols. Regioselective ring openings of 2-azirine followed by in situ aromatization using a catalytic amount of Brønsted acid have established the novelty of the methodology. The involvement of a series of 2-azirines with a variety of phenols, 1-naphthols, and 2-naphthols showed the generality of the protocol.

Effects of microRNA-mediated negative feedback on gene expression noise.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post-transcriptionally in eukaryotes by binding with target mRNAs and preventing translation. miRNA-mediated feedback motifs are ubiquitous in various genetic networks that control cellular decision making. A key question is how such a feedback mechanism may affect gene expression noise.

Exploring and exploiting the host cell autophagy during Mycobacterium tuberculosis infection.

Tuberculosis, caused by Mycobacterium tuberculosis, is a fatal infectious disease that prevails to be the second leading cause of death from a single infectious agent despite the availability of multiple drugs for treatment. The current treatment regimen involves the combination of several drugs for 6 months that remain ineffective in completely eradicating the infection because of several drawbacks, such as the long duration of treatment and the side effects of drugs causing non-adherence of patients to the treatment regimen. Autophagy is an intracellular degradative process that eliminates pathogens at the early stages of infection.

GC-MS-Guided Antimicrobial Defense Responsive Secondary Metabolites from the Endophytic Fusarium solani Isolated from Tinospora cordifolia and Their Multifaceted Biological Properties.

Medicinal plants are hosts to an infinite number of microorganisms, commonly referred to as endophytes which are rich in bioactive metabolites yielding favorable biological activities. The endophytes are known to have a profound impact on their host plant by promoting the accumulation of secondary metabolites which are beneficial to humankind. In the present study, the fungal endophyte, Fusarium solani (ABR4) from the medicinal plant Tinospora cordifolia, was assessed for its bioactive secondary metabolites employing fermentation on a solid rice medium.

Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis.

In TB, combat between the human host and Mycobacterium tuberculosis involves intricate interactions with immune cells. M. tuberculosis has evolved a complex evasion system to circumvent immune cells, leading to persistence and limiting its clearance by the host.

Unravelling the flexibility of an escape way for the bacilli.

The persistence of makes it difficult to eradicate the associated infection from the host. The flexible nature of mycobacteria and their ability to adapt to adverse host conditions give rise to different drug-tolerant phenotypes. Granuloma formation restricts nutrient supply, limits oxygen availability and exposes bacteria to a low pH environment, resulting in non-replicating bacteria.

Role of transcription termination factor Rho in anti-tuberculosis drug discovery.

Mycobacterial infections, including multidrug and extreme drug-resistant (MDR and XDR) infections, are a severe challenge and create a virtual antibiotic-deficient era. Bacterial transcription is an established antimicrobial drug target. In mycobacteria, efficient transcription termination relies on the ATP-dependent RNA helicase factor Rho.

(3 + 2) cycloaddition of 2-alkoxynaphthalenes with azaoxyallyl cations: access to benzo[]indolones.

A reaction between 2-alkoxynaphthalene and an formed azaoxyallyl cation has been reported under ambient reaction conditions. The (3 + 2) cycloaddition reaction followed by aryl C-OMe/C-OEt bond cleavage produces a variety of benzo[]indolone derivatives. Based on the isolated intermediate from the control experiment and previous results, a possible mechanism has been drawn.

An evolutionary divergent thermodynamic brake in ZAP-70 fine-tunes the kinetic proofreading in T cells.

T cell signaling starts with assembling several tyrosine kinases and adapter proteins to the T cell receptor (TCR), following the antigen binding to the TCR. The stability of the TCR-antigen complex and the delay between the recruitment and activation of each kinase determines the T cell response. Integration of such delays constitutes a kinetic proofreading mechanism to regulate T cell response to the antigen binding.