Comparative Hydrophobicity, Solubility, and Metabolic Stability of 4(1)-Pyridones, 4(1)-Quinolones, and 9(10)-Acridones.

The relatively polar 4(1)-pyridone (4-pyridone) heterocycle is found in many drugs and drug candidates. In a comparison of the hydrophobicity, aqueous solubility, and metabolic stability of several matched sets of 4-pyridones, 4(1)-quinolones (4-quinolones), and 9(10)-acridones (9-acridones), measured chromatographic log values show that 9-acridones are more hydrophobic and less soluble than their 4-quinolone and 4-pyridone counterparts. All 4-pyridone/4-quinolone pairs had identical or very similar hydrophobicity and aqueous solubility properties.

Synthesis of Triazolo[4',5':4,5]furo[2,3-]pyridine via Post Modification of an Unusual Groebke-Blackburn-Bienaymé Multicomponent Reaction.

The Groebke-Blackburn-Bienaymé (GBB) reaction is a well-established three-component reaction for synthesizing imidazofused scaffolds from heterocyclic amidines, aldehydes, and isonitriles. However, the replacement of pyridoxal as an aldehyde component in this reaction results in the formation of the furo[2,3-]pyridine skeleton as an "unusual GBB product". Despite the interesting nature of this unusual reaction, not much work was further reported.

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

Lipopeptides including diacylated PamCSK as well as triacylated PamCSK act as ligands of toll-like receptor (TLR)-2, a promising target for the development of vaccine adjuvants. The highly investigated PamCSK and PamCSK, despite their aqueous solubility have not performed well as vaccine adjuvants which may be attributable to potential denaturation of protein antigens by these cationic surfactant-like lipopeptides. In the present investigation, we synthesized (), () and racemic PamCS(OMe) analogs and their -acetyl derivatives without the tetralysine component to systematically investigate the effect of stereochemistry at the thio-glycerol lipopeptide core of these lipopeptide based TLR2 agonists.

Combined delivery of TLR2 and TLR7 agonists by Nanostructured lipid carriers induces potent vaccine adjuvant activity in mice.

Toll-like receptor (TLR) agonists are promising adjuvants and the combination of TLR agonists enhance immune responses by providing synergistic immune activity via triggering different signalling pathways. However, systematic cytotoxicity due to the immediate release of such immune potentiators from the site of injection hampers its clinical performance. Nanostructured lipid carriers (NLCs) offer a possibility to incorporate multiple TLR agonists with high encapsulation efficiency and slow drug release.

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

Several synthetic heterocyclic small molecules like imiquimod, resiquimod, CL097, CL075, bromopirone, tilorone, loxoribine and isatoribine demonstrated TLR7/8 agonistic activity and relatively modest structural changes in such molecules result in major variation in the TLR7 and/or TLR8 activity. A strict dependency of the electronic configuration of the heterocyclic system was also observed to influence the agonistic activity. In the present review, 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.

Toll-like receptor-7/8 agonist kill Leishmania amazonensis by acting as pro-oxidant and pro-inflammatory agent.

Objectives: Evaluation of the anti-Leishmanial activity of imidazoquinoline-based TLR7/8 agonists.

Methods: TLR7/8-active imidazoquinolines (2 and 3) were synthesized and assessed for activity against Leishmania amazonensis-intracellular amastigotes using mouse peritoneal macrophages. The production of reactive oxygen species (ROS), nitric oxide (NO) and cytokines was determined in infected and non-infected macrophages.

TLR2 Agonistic Small Molecules: Detailed Structure-Activity Relationship, Applications, and Future Prospects.

Toll-like receptors (TLRs) are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) in microbial species. Among the various TLRs, TLR2 has a special place due to its ability to sense the widest repertoire of PAMPs owing to its heterodimerization with either TLR1 or TLR6, broadening its ligand diversity against pathogens. Various scaffolds are reported to activate TLR2, which include naturally occurring lipoproteins, synthetic lipopeptides, and small heterocyclic molecules.

BBIQ, a pure TLR7 agonist, is an effective influenza vaccine adjuvant.

Better adjuvants are needed for vaccines against seasonal influenza. TLR7 agonists are potent activators of innate immune responses and thereby may be promising adjuvants. Among the imidazoquinoline compounds, 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (BBIQ) was reported to be a highly active TLR7 agonist but has remained relatively unexplored because of its commercial unavailability.

Efficacy of TLR7 agonistic imidazoquinoline as immunochemotherapeutic agent against P. Berghei ANKA infected rodent host.

Malaria is a serious disease and is one of the most alarming public health issues. Plasmodium is being resistant to various antimalarials including Chloroquine (CQ) which was the first-line therapy for malaria treatment. WHO recommended several combination therapies but declining efficacy was reported to many of these therapies.