Further exploration of the structure-activity relationship of imidazoquinolines; identification of potent C7-substituted imidazoquinolines

Hunt, Jordan R.; Kleindl, Peter Alan; Moulder, Kevin; Prisinzano, Thomas E.; Forrest, M. Laird

doi:10.1016/j.bmcl.2019.126788

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…As outlined in Scheme 1, compounds 5a−c were treated with 70% HNO 3 in propionic acid to obtain the 3-nitroquinolinols (6a−c). 42 Next, 6a−c were chlorinated using POCl 3 and the products 7a−c were obtained via carefully quenching the excess POCl 3 . In the next step, the ipsodisplacement of chloro functionality with substituted benzyl amines were carried out.…”

Section: Resultsmentioning

confidence: 99%

“…The synthesis was started from the commercially available quinolin-4-ol ( 5a ) and its methoxy derivatives ( 5b and 5c ). As outlined in Scheme , compounds 5a – c were treated with 70% HNO 3 in propionic acid to obtain the 3-nitroquinolinols ( 6a – c ) . Next, 6a – c were chlorinated using POCl 3 and the products 7a – c were obtained via carefully quenching the excess POCl 3 .…”

Section: Resultsmentioning

confidence: 99%

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

Kumar,

Sihag,

Patil

et al. 2024

ACS Pharmacol. Transl. Sci.

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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 (EC 50 = 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 (EC 50 = 0.15 μM in TLR7) than BBIQ and induced double the IgG response to SARS-CoV-2 and hepatitis antigens. Similarly, compound 12c (EC 50 = 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 (EC 50 = 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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Kumar,

Sihag,

Patil

et al. 2024

ACS Pharmacol. Transl. Sci.

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“…In 2019, Hunt et al 77 reported a library of compounds to explore the C-7 aryl position by imposing different electrondonating groups (EDGs) and electron-withdrawing groups (EWGs) as well as hydrogen acceptors and donors such as cyano (40), chloro (41), methoxy (42), and hydroxy (43), whereas the substitutions on N-1 and C-2 were based on the previously known SAR. In general, the SAR indicated that the EDGs at the 3.5.…”

Section: Structural Evolution and Structure−activity Relationship Of ...mentioning

confidence: 99%

Structural Evolution and Translational Potential for Agonists and Antagonists of Endosomal Toll-like Receptors

et al. 2021

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Toll-like receptors (TLRs) are members of a large family of evolutionarily conserved pattern recognition receptors (PRRs), which serve as key components of the innate immune system by playing a pivotal role in sensing "nonself" ligands. Endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) can recognize pathogen-derived nucleic acid and initiate an innate immune response because they react against both self-and non-self-origin nucleic acid molecules. Accordingly, both receptor agonists and antagonists are potentially useful in disparate clinical contexts and thus are globally sought after. Recent research has revealed that agonists and antagonists share an overlapping binding region. This Perspective highlights rational medicinal chemistry approaches to elucidate the structural attributes of small molecules capable of agonism or antagonism or of elegantly switching between the two. The structural evolution of different chemotypes can provide the framework for the future development of endosomal TLR agonists and antagonists.

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“…The fruitful combination of these two pharmacophores could achieve imidazoquinoline derivatives and be utilized for various applications, such as modulating the phosphodiesterase and adenosine A3 receptors, high toll-like receptor 7/8 (TLR7/TLR8) selective agonists, anticancer efficacy, etc. [ 14 , 15 ]. Molecular docking studies are used as a potential tool to identify the various TLR and other residues interacting with small molecular imidazoquinoline derivatives [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antibacterial, anti-oxidant and molecular docking studies of imidazoquinolines

Velmurugan

Don

Kannan

et al. 2021

Heliyon

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Quinoline and imidazole derivatives have been playing a significant role in functional bioactivities and were potentially used as antibacterial, antifungal, anticancer, and anti-inflammatory drugs. Owing to the limitation of drug resistance, herein we synthesized thio-, chloro-, and hydroxyl-functionalized various imidazoquinolines by molecular hybridization approach. All the imidazoquinoline derivatives were examined for their antibacterial activity against selected bacterial pathogens by the agar well diffusion method. In addition, the anti-oxidant efficacy of imidazoquinolines was also tested using ferric reducing antioxidant power (FRAP). Among them, electron-withdrawing (-Cl) substituent containing imidazoquinoline 5f showed higher antibacterial and antioxidant activities than other imidazoquinolines and reached the effectiveness of the standard. In addition, compounds 4f, 5e, and 3f showed moderate antibacterial activity and other derivatives displayed weak activity against various pathogens. Molecular docking studies were also performed on selected imidazoquinoline derivatives (3f, 4f, and 5f), which showed high docking score and strong binding energy values. These results revealed that thio-imidazoquinoline could assist as a prototype for the designing of multidrug-resistant antibiotics against various microbial organisms.

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Further exploration of the structure-activity relationship of imidazoquinolines; identification of potent C7-substituted imidazoquinolines

Cited by 5 publications

References 33 publications

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

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

Structural Evolution and Translational Potential for Agonists and Antagonists of Endosomal Toll-like Receptors

Synthesis, antibacterial, anti-oxidant and molecular docking studies of imidazoquinolines

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