HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells

Abstract

By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.

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

“…This is in accordance with results previously reported for the linear series of tertiary alcohol inhibitors, e.g., comparing the B (26) and C (27) series (Figure 1). However, with the p -phenyl or p- 4-pyridyl groups in the P1′ position, submicromolar values of EC 50 were observed in the antiviral cell based assay ( 19b and 19d ).…”

“…24,27,28 With the linear two-carbon spacer the 2-, 3-, and 4-pyridinyls gave equipotent inhibitors. 26 This result was also obtained with the lactam-containing inhibitors with the three-carbon extended PIs in the 19 series.…”

“…23−28 Class B , with the two-carbon spacer, yielded the best results, with values of K i and EC 50 as low as 1 and 3 nM, respectively. 26 In all three series ( A – C ), inhibitors with high membrane permeability were identified, as well as inhibitors with good metabolic stability, 23−28 providing pharmacokinetic properties well in the range of HIV PIs already on the market, e.g., ATZ. 23 …”

Microwave‐Heated Transition Metal‐Catalyzed Coupling Reactions

“…In a recent example reported by Hallberg and co-workers, a microwave-accelerated Stille coupling was used to prepare a potent HIV-1 protease inhibitor with good antiviral activity (Scheme 15.50, EC 50 = 7 nM) [113]. The inhibitor was synthesized in a moderate yield (40%) by treating an aryl bromide precursor with 2-pyridyltributyltin, Pd(PPh 3 ) 2 Cl 2 , and CuO at 120 • C for 50 min (Scheme 15.50).…”

Microwave-assisted synthesis of thermo- and pH-responsive antitumor drug carrier through reversible addition–fragmentation chain transfer polymerization

“…For example, Imatinib (Gleevec), a marketed anticancer drug, can be produced through microwave heating in five steps with shorter reaction times and higher yields than what can be obtained through traditional heating methods [5]. Various inhibitors and pharmaceutical molecules have been synthesized through microwave-assisted synthetic protocols to treat infectious diseases such as tuberculosis, HIV/AIDS, malaria, and hepatitis C [6][7][8][9]. Other notable examples, including biologically active heterocycles for Sildenafil analogs [10,11], nontoxic biofilm inhibitors (antimicrobial derivatives) [12,13], sirtuin 2-selective inhibitors [14,15], crosscoupling reactions [16,17], and positron emission tomography [18,19], have also been reported, and some reactions have been evaluated in a scale-up fashion [20,21].…”