Syntheses and anti-HIV and human cluster of differentiation 4 (CD4) down-modulating potencies of pyridine-fused cyclotriazadisulfonamide (CADA) compounds
- Bioorg Med Chem. 2020 Dec 15;28(24):115816. doi: 10.1016/j.bmc.2020.115816.
- 1. Department of Chemistry, University of Nevada, Reno, NV 89557-0216, USA.
- 2. KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, 3000 Leuven, Belgium.
- 3. Department of Chemistry, University of Nevada, Reno, NV 89557-0216, USA; Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
- 4. Department of Chemistry, University of Nevada, Reno, NV 89557-0216, USA. Electronic address: [email protected].
CADA compounds selectively down-modulate human cell-surface CD4 protein and are of interest as HIV entry inhibitors and as drugs for asthma, rheumatoid arthritis, diabetes and some cancers. Postulating that fusing a pyridine ring bearing hydrophobic substituents into the macrocyclic scaffold of CADA compounds may lead to potent compounds with improved properties, 17 macrocycles were synthesized, 14 with 12-membered rings having an isobutylene head group, two arenesulfonyl side arms, and fused pyridine rings bearing a para substituent. The analogs display a wide range of CD4 down-modulating and anti-HIV potencies, including some with greater potency than CADA, proving that a highly basic nitrogen atom in the 12-membered ring is not required for potency and that hydrophobic substituents enhance potency of pyridine-fused CADA compounds. Cytotoxicities of the new compounds compared favorably with those of CADA, showing that incorporation of a pyridine ring into the macrocyclic scaffold can produce selective compounds for potently down-modulating proteins of medicinal interest.