A novel series of beta-(thiosemicarbazide/thiosemicarbazone)-sulfide derivatives (6a - i and 8a - k) was synthesized through a streamlined multi-step approach designed to yield new antibacterial candidates. Structural elucidation was accomplished using comprehensive spectroscopic techniques. The antibacterial efficacy of the synthesized compounds was evaluated via minimum inhibitory concentration (MIC) assays against multiple bacterial strains. Notably, compounds 6d, 6e, and 6 h demonstrated potent and selective activity against Klebsiella pneumoniae (K. pneumoniae) with MIC values of 50 & micro;g/mL, compared to the reference drug ciprofloxacin (MIC >= 32 & micro;g/mL). These compounds also exhibited significant antioxidant activity in DPPH radical scavenging assays, with inhibition ranging from 75.13% to 83.74%, approaching that of ascorbic acid (87.5%). Molecular docking studies further supported their potential, revealing stable binding interactions with the active sites of K. pneumoniae topoisomerase IV and carbapenemase enzymes. Collectively, these findings highlight the dual antibacterial and antioxidant potential of the synthesized derivatives, positioning them as promising candidates for further development, particularly against multidrug-resistant K. pneumoniae.

Cancer is a significant global health challenge and the second leading cause of death worldwide, responsible for millions of fatalities annually. Despite advances in diagnostics and treatments in cancer, complexities like tumor biology, drug resistance, and toxicity limit its effective management. Herein, we focused on new imidazo-pyridine/pyrazine-fused bicyclic heterocycles. The anticancer potential of the identified bicyclic heterocycles against colorectal cancer (CRC) is established utilizing a multi-faceted approach integrating in silico network pharmacology, ADMET profiling and in vitro cytotoxicity assay. Network pharmacology analysis using the test compounds and CRC cell lines (HCT-116 and CT-26) revealed important molecular targets, such as HSP90AA1, SRC, and PIK3R1 which plays an important role in signaling pathways like PI3K/AKT and MAPK in CRC progression. Gene ontology and KEGG pathway enrichment analyses highlighted the ability of the target compounds to modulate biological processes involved in cell proliferation, apoptosis, and oxidative stress in CRC pathogenesis. ADMET profiling through GastroPlus® demonstrated that these compounds possess favorable pharmacokinetic properties, such as enhanced absorption, bioavailability, and systemic exposure. In vitro cytotoxicity studies on CRC cell lines showed dose-dependent antiproliferative effects. The findings highlight potential of imidazo-pyridine/pyrazine-fused bicyclic heterocycles as promising candidates for treating CRC.

Herein, we highlight the sequential Zn-promoted reactivity of isothiocyanates towards tertiary aliphatic amines with subsequent regioselective N-dealkylation, yielding respective thioureas. Under non-inert conditions Zn functions as a desulfurizing agent affording ZnS, while water acts as an oxygen source, facilitating the direct transformation of isothiocyanates into ureas. This strategy affords b-(thio)uredo-sulphides, important functionalities in synthetic and biological important functionalities. Through a comprehensive examination of the mechanism and substrate scope, we elucidate a non-radical pathway with Hofmann elimination as initial and desulfurization as final steps.

Imidazo based heterocyclic derivatives are considered as privileged scaffolds due to their presence in various pharmacologically active compounds and in marketed formulations. The present study reports toxicological evaluation of three imidazo based heterocyclic derivatives which are currently being investigated for their potential anticancer activity. Compounds IG-01–007, IG-01–008, and IG-01–009 were assessed for cytotoxicity, hemolysis, and DNA fragmentation activity. Acute oral toxicity studies were performed at doses of 300 mg/kg and 1000 mg/kg according to OECD guidelines, in both male and female Wistar rats. All test compounds at a concentration of 50 µM resulted in DNA fragmentation suggesting notable impact on DNA integrity. The in-vivo acute toxicity study indicated significant toxicity at doses of ≥ 1000 mg/kg, particularly for compounds IG-01–008 and IG-01–009, which caused hepatic damage and cholestasis in liver tissues. These results collectively suggest that imidazo based heterocyclic derivatives used in the present study exhibit cytotoxic potential.

INTRODUCTION:Toll-like receptors (TLRs) play a key role in cancer immunotherapy by harnessing the immune system's natural response to target and fight tumors. Among the various TLRs, mainly TLR3, TLR4, TLR7, TLR8, and TLR9, have been investigated for their ability to modulate immune responses, improve tumor recognition, and enhance the efficacy of conventional treatments like chemotherapy and radiotherapy. AREAS COVERED:This review provides an in-depth analysis of patents filed from 2014 to 2024 that explored TLR-targeting strategies in cancer therapy. TLRs trigger the release of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-12, and IL-6, which promote anti-tumor immunity by enhancing T-cell activation and dendritic cell maturation. TLR-based therapies have shown promise by stimulating innate and adaptive immunity, leading to increased tumor cell death. EXPERT OPINION:TLR agonists have been shown to, reduce treatment-related side effects, and inhibit tumor growth. However, challenges such as immune-related adverse events, including cytokine storms, and limited efficacy in specific tumor types persist. Advances in delivery systems, such as nanoparticles, liposomes, and conjugates, further enhance the targeting and effectiveness of TLR-based therapies while minimizing toxicity. The ongoing exploration of TLR agonists and their integration into combination therapies holds significant promise for improving cancer immunotherapy and patient outcomes.

Antimicrobial resistance (AMR) in gram-negative bacteria is an escalating global health crisis, rendering many traditional antibiotics ineffective. The rise of bacterial resistance has led to limited treatment options and increased mortality rates. In response, nano-antibiotics have emerged as a promising solution to combat AMR, offering novel strategies to target and neutralize resistant bacteria. Nano-antibiotics, which are typically nanoparticle-based drug delivery systems, can enhance the pharmacological properties of conventional antibiotics, improve their bioavailability, and overcome bacterial resistance mechanisms. Nanomaterials, including metal nanoparticles (NPs), carbon-based materials, and polymeric NPs, exhibit unique properties such as a high surface area, size dependent effects, and customizable surface characteristics, enabling improved drug targeting. They can disrupt bacterial cell walls, generate reactive oxygen species (ROS), and facilitate sustained release of antibiotics at the site of infection, providing an effective means to combat multidrug-resistant gram-negative pathogens. Additionally, nano-antibiotics can synergize with existing antibiotics, enhancing their efficacy at lower doses while minimizing the likelihood of side effects. Despite the promising findings in laboratory and preclinical studies, challenges such as toxicity, stability, and regulatory approval still persist. Ongoing research focused on optimizing nanoparticle formulations and surface modifications, holds great promise for the development of more effective treatments. This review explores the current progress of nano-antibiotics, their mechanism of action, potential applications, as well as the challenges and future directions in combating antimicrobial resistance in gram-negative bacteria.

A convenient methodology for C-4 indole-β-lactam hybrids with chloro, sulphur and seleno substitutions through dual site reactivity of indole-3-Schiff bases towards ketenes has been developed. The reaction proceeded in a stereospecific manner with the exclusive formation of trans-β-lactams assigned with respect to C3-H and C4-H. The synthesized novel β-lactams have been characterized with the help of elemental analysis (CHNS) and spectroscopic techniques viz. 1H NMR, 13C NMR, DEPT 135, HSQC and IR. The trans configuration was further estabilished based on X-ray crystallographic data. Examination of antibacterial properties unveiled that only derivatives 5a and 5b, featuring chloro substitution, exhibited potent activities, underscoring the emergence of the recently coined term “magic chloro effect”. Molecular docking analysis provided additional support for the observed in vitro antibacterial activities of compounds 5a-b.

Organoselenium compounds have been the subject of extensive research since the discovery of the biologically active compound ebselen. Ebselen has recently been found to show activity against the main protease of the virus responsible for COVID-19. Other organoselenium compounds are also well-known for their diverse biological activities, with such compounds exhibiting interesting physical properties relevant to the fields of electronics, materials, and polymer chemistry. In addition, the incorporation of selenium into various organic molecules has garnered significant attention due to the potential of selenium to enhance the biological activity of these molecules, particularly in conjunction with bioactive heterocycles. Iodine and iodine-based reagents play a prominent role in the synthesis of organoselenium compounds, being valued for their cost-effectiveness, non-toxicity, and ease of handling. These reagents efficiently selenylate a broad range of organic substrates, encompassing alkenes, alkynes, and cyclic, aromatic, and heterocyclic molecules. They serve as catalysts, additives, inducers, and oxidizing agents, facilitating the introduction of different functional groups at alternate positions in the molecules, thereby allowing for regioselective and stereoselective approaches. Specific iodine reagents and their combinations can be tailored to follow the desired reaction pathways. Here, we present a comprehensive review of the progress in the selenylation of organic molecules using iodine reagents over the past decade, with a focus on reaction patterns, solvent effects, heating, microwave, and ultrasonic conditions. Detailed discussions on mechanistic aspects, such as electrophilic, nucleophilic, radical, electrochemical, and ring expansion reactions via selenylation, multiselenylation, and difunctionalization, are included. The review also highlights the formation of various cyclic, heterocyclic, and heteroarenes resulting from the in situ generation of selenium intermediates, encompassing cyclic ketones, cyclic ethers, cyclic lactones, selenophenes, chromones, pyrazolines, pyrrolidines, piperidines, indolines, oxazolines, isooxazolines, lactones, dihydrofurans, and isoxazolidines. To enhance the reader's interest, the review is structured into different sections covering the selenylation of aliphatic sp2/sp carbon and cyclic sp2 carbon, and then is further subdivided into various heterocyclic molecules.

Abstract Background As the leading form of non-melanoma skin cancer, basal cell carcinoma (BCC) presents a considerable challenge to healthcare systems, owing to its widespread occurrence. Current treatment options, such as surgical excision, cryotherapy, and localized therapies like imiquimod or 5-fluorouracil, face challenges, especially in designing drug delivery systems that provide prolonged therapeutic effects. This study aims to develop bio-composite polymeric films for localized drug delivery using natural polymers, lignin, and chitosan, to enhance the delivery of the TLR7 agonist imiquimod for BCC treatment. Results The optimized biofilms were prepared by adjusting the polymer ratio and drying techniques to achieve a balanced composition for localized imiquimod delivery. FTIR and DSC characterization confirmed successful drug incorporation into the biofilms, while microscopic studies revealed the biofilms homogeneity and fibrous nature. Drug release studies demonstrated pH-dependent kinetics, with higher release rates at neutral pH. The biofilms exhibited slow and sustained drug release, promising prolonged therapeutic effects. Additionally, the biofilms were non-hemolytic, showed significant antioxidant activity, and demonstrated selective cytotoxicity against B16–F10 mouse skin melanoma cells. Conclusions This study suggests that lignin-chitosan-based imiquimod-loaded biofilms hold potential as an effective topical treatment for BCC. The biofilm’s ability to provide sustained drug release, along with their biocompatibility and selective cytotoxicity, indicates a promising approach to enhancing BCC therapy. Graphical abstract

The enantioselective synthesis of chiral cis-3-hydroxyazetidin-2-ones mediated by Porcine Pancreatic Lipase (PPL) via hydrolysis of cis-3-(chloro acetoxy) azetidin-2-ones in the presence of a phosphate buffer (0.1M, pH = 7.2) in acetonitrile at a temperature range of 25-35 degrees C was optimized. Under the optimized reaction conditions, the influence of various electron withdrawing/donating/neutral groups on ester functionality of cis-3-(substituted acetoxy)azetidin-2-ones towards hydrolysis was extensively studied, and the bromoacetoxy, propanyloxy, and formyloxy groups provided moderate to good yields of 90%, 91%, and 81%, respectively. Moreover, the chiral cis-3-hydroxyazetidin-2-ones underwent acetylation, and their enantiomeric excess was assessed using the 1H NMR technique, employing chiral shift reagents. To gain insights into the active sites of the biocatalyst, molecular docking studies of compounds 5(a-i) with pancreatic lipase (PDB ID: 1LBS) were carried out. Additionally, the proposed interaction of substituents with the biocatalyst established the absolute stereochemistry of the target chiral cis-3-hydroxyazetidin-2-ones using Seebach's model in comparison to Jone's models.

Herein, we showcase the potential of isothiocyanates generated in situ and aryl sulfonyl chlorides as electrophiles in water for N-functionalization of bicyclic amidines (DBN and DBU). This strategy provides complementary access to a range of thiouredosulfides, sulfonamides, aroylthioureas and amides derivativatized with distal γ- and ω-lactams. A novel sulfonyl chloride mediated formation of β-uredo sulfides has been achieved from β-isothiocyanato sulfides, removing the requirement for the harsh synthesis of unstable isocyanates. Mechanistic studies suggest a radical mechanism for the difunctionalization of alkenes, the efficacy of H2O in the ring opening of bicyclic amidines, and an oxygen source along with sulfonyl chloride as desulfurization agents for thiourea to afford urea derivatives.

Herein, a novel synthetic methodology was devised to synthesize cis -3-aroyl-thiourea/urea-β-lactams by reacting aroyl isothiocyanates/isoselenocyanates with cis -3-amino-β-lactams.

The present work describes the synthesis of cis-3-(substituted acetoxy)azetidin-2-ones from cis-3-hydroxyazetidin-2-ones. Two different routes have been investigated for the substitution at the C-3 position of the azetidin-2-ones. Method A involves the use of acetyl chloride XCOCl in the presence of pyridine and method B consists of using appropriate acid XCOOH in a catalytic amount of DMAP which was found to be the best to furnish the target azetidin-2-one. All the newly synthesized compounds were characterized on the basis of various spectroscopic techniques (FT-IR, H-1 NMR, C-13 NMR, and elemental analysis). Two different routes have been investigated for the substitution at the C-3 position of the azetidin-2-ones.

A sulfonyl promoted synthetic protocol for the C-3 alkylation of trans-3-phenylsulfonyl-beta-lactams 6(a-e) with active organic halides in presence of K2CO3 as mild base and DMF as solvent is described. This protocol furnished cis- and trans-beta-lactams as major and minor isomers respectively with alkyl halides while arylalkyl/unsaturated halides yield only cis-beta-lactams exclusively. Further, the effect of sterically bulky group on the C-3 substitution was investigated by the reaction of 3-phenylsulfonyl-beta-lactams 6(d-e) with crotyl chloride (predominantly E) to achieve diastereomeric mixture of beta-lactams 7/7' and 8. This strategy reveals advantages in terms of cost effectiveness, functional group tolerance and ease of operation. (C) 2020 Elsevier Ltd. All rights reserved.