Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIV-1 and EV-A71 Entry Inhibitors†

  • J Med Chem. 2021 Jul 22;64(14):10027-10046. doi: 10.1021/acs.jmedchem.1c00315.
Olaia Martí-Marí  1 ,  Belén Martínez-Gualda  1 ,  Sofía de la Puente-Secades  1 ,  Alberto Mills  2 ,  Ernesto Quesada  1 ,  Rana Abdelnabi  3 ,  Liang Sun  3 ,  Arnaud Boonen  3 ,  Sam Noppen  3 ,  Johan Neyts  3 ,  Dominique Schols  3 ,  María-José Camarasa  1 ,  Federico Gago  2 ,  Ana San-Félix  1
Affiliations
  • 1. Instituto de Química Médica (IQM-CSIC), c/ Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 2. Área de Farmacología, Departamento de Ciencias Biomédicas y Unidad Asociada IQM-UAH, Universidad de Alcalá, E-28805 Alcalá de Henares, Madrid, Spain.
  • 3. Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, B-3000 Leuven, Belgium.
PMID: 34229438 DOI: 10.1021/acs.jmedchem.1c00315
Abstract

We have recently described a new generation of potent human immunodeficiency virus (HIV) and EV-A71 entry inhibitors. The prototypes contain three or four tryptophan (Trp) residues bearing an isophthalic acid moiety at the C2 position of each side-chain indole ring. This work is now extended by both shifting the position of the isophthalic acid to C7 and synthesizing doubly arylated C2/C7 derivatives. The most potent derivative (50% effective concentration (EC50) HIV-1, 6 nM; EC50 EV-A71, 40 nM), 33 (AL-518), is a C2/C7 doubly arylated tetrapodal compound. Its superior anti-HIV potency with respect to the previous C2-arylated prototype is in consonance with its higher affinity for the viral gp120. 33 (AL-518) showed comparable Antiviral activities against X4 and R5 HIV-1 strains and seems to interact with the tip and base of the gp120 V3 loop. Taken together, these findings support the interest in 33 (AL-518) as a useful new prototype for anti-HIV/EV71 drug development.