Open AccessPreclinical Optimization of gp120 Entry Antagonists as anti-HIV-1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation
Author(s) -
Francesca Curreli,
Shahad Ahmed,
Sofia M. Benedict Victor,
Ildar R. Iusupov,
Dmitry S. Belov,
Pavel O. Markov,
Alexander V. Kurkin,
Andrea Altieri,
Asim K. Debnath
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b02149
Subject(s) - adme , chemistry , cytotoxicity , combinatorial chemistry , bioavailability , stereochemistry , solubility , rational design , in vitro , pharmacology , organic chemistry , biochemistry , nanotechnology , medicine , materials science
We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 ( Ref1 ), which showed antiviral activity against HIV-1 HXB2 , with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 ( 8 ), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1 . The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.