Design and Synthesis of Polyphenolic Imidazo[4,5-c]quinoline Derivatives to Modulate Toll Like Receptor-7 Agonistic Activity and Adjuvanticity.

TLR-7/8 agonists are a well-known class of vaccine adjuvants, with a leading example now included in Covaxin, a licensed human COVID-19 vaccine. This thereby provides the opportunity to develop newer, more potent adjuvants based on structure-function studies of these classes of compounds. Imidazoquinoline-based TLR7/8 agonists are the most potent, but when used as a vaccine adjuvant side effects can arise due to diffusion from the injection site into a systemic circulation. In this work, we sought to address this issue through structural modifications in the agonists to enhance their adsorption capacity to the classic adjuvant alum. We selected a potent TLR7-selective agonist, BBIQ (EC50 = 0.85 µM), and synthesized polyphenolic derivatives to assess their TLR7 agonistic activity and adjuvant potential alone or in combination with alum. Most of the phenolic derivatives were more active than BBIQ and, except for 12b, all were TLR7 specific. Although the synthesized compounds were less active than resiquimod, the immunization data on combination with alum, specifically the IgG1, IgG2b and IgG2c responses, were superior in comparison to BBIQ as well as the reference standard resiquimod. Compound 12b was 5-fold more potent (EC50 = 0.15 µM in TLR7) than BBIQ and induced double the IgG response to SARS-CoV-2 and hepatitis antigens. Similarly, compound 12c (EC50 = 0.31 µM in TLR7) was about 3-fold more potent than BBIQ and doubled the IgG levels. Even though compound 12d exhibited low TLR7 activity (EC50 = 5.13 µM in TLR7), it demonstrated superior adjuvant results, which may be attributed to its enhanced alum adsorption capability as compared with BBIQ and resiquimod. Alum-adsorbed polyphenolic TLR7 agonists thereby represent promising combination adjuvants resulting in a balanced Th1/Th2 immune response.

Structure-Activity Relationships toward the Identification of a High-Potency Selective Human Toll-like Receptor-7 Agonist.

Toll-like receptor (TLR)-7 agonists are immunostimulatory vaccine adjuvants. A systematic structure-activity relationship (SAR) study of TLR7-active 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine led to the identification of a potent hTLR7-specific p-hydroxymethyl IMDQ 23 with an EC50 value of 0.22 µM. The SAR investigation also resulted in the identification of TLR7 selective carboxamide 12 with EC50 values of 0.32 µM for hTLR7 and 18.25 µM for hTLR8. In the vaccination study, TLR7-specific compound 23 alone or combined with alum (aluminum hydroxide wet gel) showed adjuvant activity for a spike protein immunogen in mice, with enhanced anti-spike antibody production. Interestingly, the adjuvant system comprising carboxamide 12 and alum showed prominent adjuvant activity with high levels of IgG1, IgG2b, and IgG2c in immunized mice, confirming a balanced Th1/Th2 response. In the absence of any apparent toxicity, the TLR7 selective agonists in combination with alum may make a suitable vaccine adjuvant.

Structure activity relationship in ß-carboline derived anti-malarial agents.

Malaria, even though an avoidable and treatable disease, can be fatal if ignored. Artemisinin Combination Therapy (ACT) and RTS, S/AS01 vaccine (Mosquirix™) are the only modest means available with humans to overcome malaria, a lethal affliction wreaking havoc across the globe. Employment of ACT is associated with problems such as 'Artemisinin Resistance' and the 'Hypnozoite conundrum' that hinder the complete eradication of malaria. In this view, the natural products specifically comprising ß-carboline scaffold have shown good antiplasmodial responses against different strains of malaria. Taking these observations forward, researchers have performed structure-activity relationship (SAR) studies around three different ß-carboline skeletons (tetrahydro ß-carbolines, dihydro ß-carbolines, ß-carbolines) to design new ß-carboline derived heterocyclic structures or modified naturally occurring derivatives. In addition, different approaches such as dimerization and linkage to other moieties have also been adopted to enhance the antimalarial activity. The present review describes a comprehensive SAR study encapsulating various natural and synthetic ß-carbolines to elaborate upon the utility of these skeletons in designing drugs to subdue this deadly disease.