Improved P1/P1‘ Substituents for Cyclic Urea Based HIV-1 Protease Inhibitors:  Synthesis, Structure−Activity Relationship, and X-ray Crystal Structure Analysis

Abstract

We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.

Three-Dimensional Quantitative Structure−Activity Relationship Study on Cyclic Urea Derivatives as HIV-1 Protease Inhibitors: Application of Comparative Molecular Field Analysis

“…Biological Data. The HIV-1 protease inhibitory data, represented by Ki (nM) values, are taken from the literature 32,33,45 and listed in Table 1. The log 1/Ki values were used to derive 3D-QSAR models.…”

“…To exploit the wealth of structural and biological data and to contribute toward the understanding of the SAR of HIV-1 protease inhibitors, we have undertaken systematic structure−activity analyses of inhibitors of the cyclic urea class. A large number of these inhibitors have been synthesized in a systematic manner and biologically evaluated. ,,− Nine X-ray crystal structures of cyclic urea derivatives complexed with HIV-1 protease are currently available in the PDB. Our recent success in deriving a 3D-QSAR predictive model 37 on a set of symmetrical cyclic urea derivatives against HIV-1 protease prompted us to extend the study to a larger and more diverse set of inhibitors of this class.…”

“…A large number of these inhibitors have been synthesized in a systematic manner and biologically evaluated. 31,32,[38][39][40][41][42][43][44][45] Nine X-ray crystal structures of cyclic urea derivatives complexed with HIV-1 protease are currently available in the PDB. Our recent success in deriving a 3D-QSAR predictive model 37 on a set of symmetrical cyclic urea derivatives against HIV-1 protease prompted us to extend the study to a larger and more diverse set of inhibitors of this class.…”

Lipase‐catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives

“…5-Bromo-2-mercaptobenzoxazole 42 was obtained in 3 steps including nitration of 4-bromophenol to 4bromo-2-nitrophenol, 55 reduction of 4-bromo-2-nitrophenol to 2-amino-4-bromophenol, 56 and cyclization of 2-amino-4bromophenol with carbon disulfide leading to 5-bromo-2mercaptobenzoxazole. Amano AK (lipase from Pseudomonas fluorescens), Amano PS (lipase from Burkholderia cepacia), and Amano PS-IM (lipase from B. cepacia immobilized on diatomite) were purchased from Sigma-Aldrich (Germany).…”

“…2-Mercaptobenzoxazole was purchased from Alfa Aesar GmbH & Co KG (Germany). 5-Bromo-2-mercaptobenzoxazole 42 was obtained in 3 steps including nitration of 4-bromophenol to 4bromo-2-nitrophenol, 55 reduction of 4-bromo-2-nitrophenol to 2-amino-4-bromophenol, 56 and cyclization of 2-amino-4bromophenol with carbon disulfide leading to 5-bromo-2mercaptobenzoxazole. The cyclization was performed by modification of the described method.…”