Design, synthesis, and biological evaluation of anti-HIV double-drugs: Conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers

Based on the prodrug concept as well as the combination of two different cl asses of anti-HIV agents, we designed and synthesized a series of anti-HIV double-drugs consisting of HIV protease inhibitors conjugated with a nucleo side reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoins the two di fferent classes of inhibitors has been investigated. Double-drugs using a s uccinyl amino acid linker were shown to release the parent drugs via sponta neous imide formation at a faster rate compared to compounds using a glutar yl amino acid linker, as expected from the energetically favorable cyclizat ion to the five-membered ring. Among the double-drugs, KNI-1039 (3b) with a glutaryl-glycine linker exhibited extremely potent anti-HIV activity compa red with that of the individual components. Double-drug 3b was relatively s table in culture medium, whereas it regenerated active species in cell homo genate. These results suggested that the synergistic enhancement of anti-HI V activities of 3b may be due to their ability to penetrate into the target cell and subsequent regeneration of two different classes of anti-HIV agen ts in the cytoplasm. (C) 2001 Elsevier Science Ltd. All rights reserved.