Design and Synthesis of P1–P3 Macrocyclic Tertiary-Alcohol-Comprising HIV-1 Protease Inhibitors

Abstract

To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 μM, respectively.

Base‐Promoted Coupling of Carbon Dioxide, Amines, and N‐Tosylhydrazones: A Novel and Versatile Approach to Carbamates

“…Organic carbamates constitute an important class of biologically and pharmaceutically interesting compounds that frequently occur in numerous natural products, [1] agrochemicals, [2] and medicines. [3] Representative examples, namely Prezista, [4] Lunesta, [5] and VESIcare, [6] which are used for the treatment of HIV, insomnia, and overactive bladders, respectively, are shown in Figure 1. Moreover, organic carbamates can also serve as key reagents, targetspecific intermediates, and removable protecting groups in organic synthesis.…”

Asymmetric Synthesis of Efavirenz via Organocatalyzed Enantioselective Trifluoromethylation

“…According to the 2013 UNAIDS Report on the global AIDS epidemic, new HIV infections were estimated at 2.3 million in 2011 1b. Although the number of new HIV infections in recent years is tending to decline since the peak in 2005, universal access to HIV/AIDS treatments is still urgently required to prevent AIDS‐related deaths 1c. Efavirenz, ( S )‐6‐chloro‐4‐(cyclopropylethynyl)‐1,4‐dihydro‐4‐(trifluoromethyl)‐2 H ‐3,1‐benzoxazin‐2‐one ( 1 ), a potent non‐nucleoside reverse transcriptase inhibitor of HIV‐1, was approved by the FDA in 1998, and has been used in combination with other antiretrovirals for the treatment of HIV infection in adults and children 2…”

Macrocyclic Assembly: A Dive into the Pecking Order and Applied Aspects of Multitalented Metallomacrocycles

“…Considering the fast development of resistant viral strains in general [127], there is a need for new, unique structural entities that could provide alternatives for use in future anti-HIV. Series of potent HIV-1 PIs related to both atazanavir and indinavir but encompassing a shielded tertiary alcohol as part of the transition-state-mimicking scaffold and different lengths of the central carbon spacer ( = 1−3) where tertiary alcohols were used as part of transition-state mimics in aspartyl PIs have been synthesized [128] (Figure 14). Tsantrizos and coworkers [129] have synthesized a novel class of inhibitors which could potentially provide a therapeutic agent for the treatment of hepatitis C in humans.…”