Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.
3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes and were evaluated in the Suzuki–Miyaura cross-coupling reactions.
An
electrochemical, nickel-catalyzed reductive coupling
of alkylpyridinium
salts and aryl halides is reported. High-throughput experimentation
(HTE) was employed for rapid reaction optimization and evaluation
of a broad scope of pharmaceutically relevant structurally diverse
aryl halides, including complex drug-like substrates. In addition,
the transformation is compatible with both primary and secondary alkylpyridinium
salts with distinct conditions. Mechanistic insights were critical
to enhance the efficiency of coupling using secondary alkylpyridinium
salts. Systematic comparisons of the electrochemical and non-electrochemical
methods revealed the complementary scope and efficiency of the two
approaches.
3-Aryl-2-phosphoimidazo[1,2-a]pyridine ligands were prepared via two complimentary synthetic routes and were evaluated in the Suzuki–Miyaura and Buchwald–Hartwig amination cross-coupling reactions.
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