4CPX

Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol

Summary for 4CPX

• Entry DOI: 10.2210/pdb4cpx/pdb
• Related: 4CPQ 4CPR 4CPS 4CPT 4CPU 4CPW
• Descriptor: PROTEASE, CHLORIDE ION, methyl ~{N}-[(2~{S})-3,3-dimethyl-1-[2-[3-[(3~{R},6~{S},10~{Z})-3-oxidanyl-4,7-bis(oxidanylidene)-6-propan-2-yl-5,8-diazabicyclo[11.2.2]heptadeca-1(16),10,13(17),14-tetraen-3-yl]propyl]-2-[(4-thiophen-2-ylphenyl)methyl]hydrazinyl]-1-oxidanylidene-butan-2-yl]carbamate, ... (4 entities in total)
• Functional Keywords: hydrolase, inhibitor, rational drug design
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS
• Total number of polymer chains: 2
• Total formula weight: 22389.62

Authors

DeRosa, M.,Unge, J.,Motwani, H.V.,Rosenquist, A.,Vrang, L.,Wallberg, H.,Larhed, M. (deposition date: 2014-02-08, release date: 2014-12-17, Last modification date: 2024-05-01)

Primary citation

De Rosa, M.,Unge, J.,Motwani, H.V.,Rosenquist, A.,Vrang, L.,Wallberg, H.,Larhed, M.
Synthesis of P1'-functionalized macrocyclic transition-state mimicking HIV-1 protease inhibitors encompassing a tertiary alcohol.
J. Med. Chem., 57:6444-6457, 2014

PubMed Abstract: Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macrocyclization, 14- and 15-membered macrocyclic PIs were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 10f, with a 2-thiazolyl group in the P1' position, was the most potent PI of this new series (Ki 2.2 nM, EC50 0.2 μM). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed.

PubMed: 25054811
DOI: 10.1021/jm500434q

Experimental method

X-RAY DIFFRACTION (1.85 Å)