Two-Carbon-Elongated HIV-1 Protease Inhibitors with a Tertiary-Alcohol-Containing Transition-State Mimic

Abstract

A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

“…Inhibitor 72 (Figure 42), with a 4-pyridyl extension of the aryl system, displayed good activity with a K i of 2.8 nM and an EC 50 of 0.17 µM. 133 The 3-pyridyl derivative 73 showed similar activity, with a K i of 5 nM and an EC 50 of 0.18 µM. 134 Inhibitor 73 showed excellent cellular permeability with a Caco-2 P app of 33 × 10 −6 cm/s.…”

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

“…39,40 1,4-Addition of triethyl phosphite to compounds 4a-d in the presence of phenol resulted in formation of the acetal intermediates which were then hydrolysed to aldehydes 5a-d. Next compound 5b was reacted with 3-pyridine boronic acid and 2-thiophene boronic acid in a microwave-assisted Suzuki coupling. 41 Using the Pd(Pt-Bu 3 ) 2 catalyst in the reaction with 3-pyridine boronic acid and the Pd(OAc) 2 /[(t-Bu 3 )HP]BF 4 combination in the reaction with 2-thiophene boronic acid, compounds 5e and 5f were obtained in satisfactory yields (35% and 41%, respectively).…”

Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

“…Thus, to introduce the 2-pyridyl as a para-substituent in P1′, the 2-pyridine-substituted hydrazide 5b (Scheme 6) was synthesized starting from the 4-(2-pyridinyl)benzaldehyde, as previously described. 27 …”

“…23−28 Inspired by the structure of the potent inhibitor Atazanavir (ATZ) 29,30 (Figure 1), we used a similar hydrazide moiety in the prime side 31 of our new tert -hydroxy-containing PIs. By altering the length of the central backbone, using a one-, two-, or three-carbon spacer (Figure 1, series A , 23−25 B , 26 and C , 27,28 respectively), we focused on optimizing the interaction with the catalytically active aspartic acid residues of the enzyme.…”

“…Spacers are indicated in red: A , one-carbon spacer ( K i = 5.5 nM); 23−25 B , two-carbon spacer ( K i = 2.3 nM); 26 C , three-carbon spacer ( K i = 2.8 nM); 27 D , novel lactam-based inhibitors with two-carbon spacer ( K i = 0.8 nM) and altered stereocenters indicated by asterisks; E , three-carbon spacer ( K i = 4.2 nM). ATZ is included for comparison ( K i = 2.7 nM).…”