CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1−34) were synthesized, displaying CCR5-antagonist activities in the 2.3−296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 Å resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 μM, which overcomes the potential drug−drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.

In this study we developed a method for the pyridine-directed, rhodium-catalyzed, site-selective C-H alkylation and arylation of pyridones using commercially available trifluoroborate reagents. This simple and versatile transformation proceeded smoothly under relatively mild conditions with perfect site selectivity. The coupling groups in the boron reagents can be extended to primary alkyl, benzyl, and cycloalkyl. Moreover, direct C-H arylation products could also be obtained under similar conditions.

The Cu(II)-catalyzed and chelate-directed C6-selective C-H thiolation of 2-pyridones with disulfides was developed to provide aryl and alkyl thioethers. This transformation uses a catalytic amount of Cu(OAc) 2 and molecular oxygen in air as an oxidant, no cocatalysts or metallic oxidants are required. The reaction accommodated both electronic and steric factors at the C3-C5 positions of 2-pyridones, which is efficient for the C6 thiolation of a broad range of 2-pyridones with up to 93% yield.