Structural evolution of toll-like receptor 7/8 agonists from imidazoquinolines to imidazoles

TLR7/8 agonists are emerging as promising vaccine adjuvant candidates. An evolution of imidazole based TLR7/8 agonist from imidazoquinoline based scaffold is delineated along with the elaboration of detailed structure activity relationship (SAR) in each chemotype.</p

Dual immunomodulatory and antileishmanial potential of TLR7/8 agonists against Leishmania donovani

ABSTRACT Visceral leishmaniasis (VL), caused by Leishmania donovani, is a neglected tropical disease with limited therapeutic options and increasing drug resistance. This study investigates the immunological mechanisms and antiparasitic efficacy of imidazoquinoline-based Toll-like receptor 7/8 (TLR7/8) agonists as host-directed agents in an in vitro VL model. Using RAW 264.7 macrophages and L. donovani promastigotes and amastigotes, we examined macrophage activation, nitric oxide (NO) induction, and cell cycle disruption in parasites. The lead compounds (5 and 10) significantly enhanced NO production in macrophages, both in unstimulated and LPS-stimulated conditions, indicating robust innate immune activation. Additionally, parasite-derived reactive oxygen species (ROS) levels were markedly elevated, suggesting oxidative stress as a mechanism of direct leishmanicidal action. Flow cytometric analysis revealed G0/G1 arrest in treated promastigotes, further supporting interference with parasite proliferation. Importantly, these compounds exhibited low cytotoxicity toward host cells and favorable selectivity indices. Notably, this is the first in vitro study to comprehensively demonstrate the ability of TLR7/8 agonists to exert direct parasiticidal effects along with immune modulation in the context of VL. The results underscore the potential of TLR-targeted immunomodulation to enhance host defense mechanisms against intracellular protozoan infections and contribute to the development of novel immunopharmacological interventions for VL

Lignin-chitosan-based biocomposite film for the localized delivery of TLR7 agonist imiquimod

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 abstrac

Stereoisomeric Pam₂CS based TLR2 agonists: synthesis, structural modelling and activity as vaccine adjuvants

Lipopeptides including diacylated Pam2CSK4as well as triacylated Pam3CSK4act as ligands of toll-like receptor (TLR)-2, a promising target for the development of vaccine adjuvants.</jats:p