C-3 Benzoic Acid Derivatives of C-3 Deoxybetulinic Acid and Deoxybetulin as HIV-1 Maturation Inhibitors

Publication date: Available online 2 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Zheng Liu, Jacob J. Swidorski, Beata Nowicka-Sans, Brian Terry, Tricia Protack, Zeyu Lin, Himadri Samanta, Sharon Zhang, Zhufang Li, Dawn D. Parker, Sandhya Rahematpura, Susan Jenkins, Brett R. Beno, Mark Krystal, Nicholas A. Meanwell, Ira B. Dicker, Alicia Regueiro-Ren
A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50 = 16 nM for 9a compared to 10 nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2^nd generation MI.

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