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a b s t r a c tThe discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

Imiquimod is an immune response modifier currently used as a topical treatment of genital warts, basal cell carcinoma, cutaneous metastasis of malignant melanoma, and vascular tumors. We developed more efficient killers from the same family of compounds that can induce apoptosis without the prominent proinflammatory response associated with imiquimod. Among these new products, tk;4EAPB0203, a member of the imidazo IntroductionImiquimod, the first member of the imidazoquinolone family, is an immune response modifier with potent antiviral and antitumor activity in vivo. This product is currently approved as a topical treatment of external genital warts caused by human papilloma virus. [1][2][3] Recent evidence suggests that imiquimod is also efficacious as a topical therapy for basal cell carcinoma, intraepidermal keratinocyte neoplasias, cutaneous metastasis of malignant melanoma, and vascular tumors. 4,5 Moreover, imiquimod applied systemically in animal experiments has proven efficacy in a variety of transplantable tumors, including colon carcinomas, melanomas, lung sarcomas, mammary carcinomas, and bladder carcinomas. [6][7][8] It has been shown that imiquimod exerts its antiviral and antitumor effects in vivo, primarily by stimulating both the innate and adaptive immune responses. Imiquimod effects are mediated by the secretion of proinflammatory cytokines, including interferon-␣, interferon gamma, interleukin 6, interleukin 12, and tumor necrosis factor-␣. 9 However, recent in vitro studies showed that imiquimod, at clinically achievable concentrations, directly induces apoptosis in malignant keratinocytes and malignant melanoma cells, in the absence of immune cells. Furthermore, melanoma cell lines derived from imiquimod-resistant cutaneous metastasis, were also resistant to imiquimod in vitro. Interestingly, normal primary human melanocytes are resistant to imiquimod. 10 However, because imiquimod induces a significant proinflammatory response and stimulates the production of proinflammatory cytokines that can exert deleterious effects, more efficient killers from the same family of compounds, which can induce apoptosis without a prominent proinflammatory response, are needed. In a previous study, we designed and analyzed a series of imidazo[1,2-a]quinoxalines, as possible imiquimod analogues. We found that, contrary to imiquimod, these imidazo[1,2-a]quinoxalines inhibit both the production and the effects of tumor necrosis factor-␣; hence, these imiquimod antagonists can be considered as potential anti-inflammatory drugs. 11 Among these new products, EAPB0203 exhibits an important cytotoxic activity in vitro and is 50 times more potent than imiquimod against a human melanoma cell line (G.M. et al, unpublished data, 2007).The retrovirus HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL), an aggressive malignancy of CD4 ϩ T lymphocytes. 12 ATL is preceded by oligoclonal expansions of HTLV-I-infected activated T cells 13 as a result of the viral transactivator protein Tax expression, whic...

The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine adjuvants. However, the chronic immune activation by excessive TLR stimulation is a hallmark of several clinically important infectious and autoimmune diseases, which warrants the search for TLR antagonists. In this study, we have synthesized and characterized a variety of compounds belonging to three heterocyclic chemical series: imidazo­[1,2-a]­pyrazine, imidazo­[1,5-a]­quinoxaline, and pyrazolo­[1,5-a]­quinoxaline. These compounds have been tested for their TLR7 or TLR8 agonistic and antagonistic activities. Several of them are shown to be selective TLR7 antagonists without any TLR7 or TLR8 agonistic activity. The selectivity was confirmed by a comparative ligand-docking study in TLR7 antagonist pocket. Two compounds of the pyrazolo­[1,5-a]­quinoxaline series (10a and 10b) are potent selective TLR7 antagonists and may be considered as promising starting points for the development of new therapeutic agents.