BIOMAT Database Logo BIOMAT Database Logo

Potent HIV-1 protease inhibitors incorporating squaramide-derived P2 ligands: Design, synthesis, and biological evaluation. 2019

Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. Electronic address: akghosh@purdue.edu.

We describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing a squaramide-derived scaffold as the P2 ligand in combination with a (R)-hydroxyethylamine sulfonamide isostere. Inhibitor 3h with an N-methyl-3-(R)-aminotetrahydrofuranyl squaramide P2-ligand displayed an HIV-1 protease inhibitory Ki value of 0.51 nM. An energy minimized model of 3h revealed the major molecular interactions between HIV-1 protease active site and the tetrahydrofuranyl squaramide scaffold that may be responsible for its potent activity.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D011803 Quinine An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. Biquinate,Legatrim,Myoquin,Quinamm,Quinbisan,Quinbisul,Quindan,Quinimax,Quinine Bisulfate,Quinine Hydrochloride,Quinine Lafran,Quinine Sulfate,Quinine Sulphate,Quinine-Odan,Quinoctal,Quinson,Quinsul,Strema,Surquina,Bisulfate, Quinine,Hydrochloride, Quinine,Sulfate, Quinine,Sulphate, Quinine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004988 Ethers, Cyclic Compounds of the general formula R-O-R arranged in a ring or crown formation. Cyclic Ether,Cyclic Ethers,Ether, Cyclic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D016333 HIV Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Proteinase,HTLV-III Protease,p16 pol gene product, HIV,p16 protease, HIV,HIV p16 protease,HTLV III Protease,Protease, HIV,Protease, HTLV-III
D017320 HIV Protease Inhibitors Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly. HIV Protease Inhibitor,Inhibitor, HIV Protease,Inhibitors, HIV Protease,Protease Inhibitor, HIV,Protease Inhibitors, HIV

Related Publications

Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands.
June 2011, Bioorganic & medicinal chemistry letters,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Design and synthesis of highly potent HIV-1 protease inhibitors with novel isosorbide-derived P2 ligands.
June 2014, Bioorganic & medicinal chemistry letters,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.
October 2017, Bioorganic & medicinal chemistry,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies.
October 2008, Organic & biomolecular chemistry,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands.
February 2010, Bioorganic & medicinal chemistry letters,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands.
September 2014, Organic & biomolecular chemistry,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Design and synthesis of novel HIV-1 protease inhibitors incorporating oxyindoles as the P2'-ligands.
April 2006, Bioorganic & medicinal chemistry letters,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P(2) ligands: structure-activity studies and biological evaluation.
January 2011, Journal of medicinal chemistry,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
August 1996, Journal of medicinal chemistry,
Arun K Ghosh, and Jacqueline N Williams, and Satish Kovela, and Jun Takayama, and Hannah M Simpson, and D Eric Walters, and Shin-Ichiro Hattori, and Manabu Aoki, and Hiroaki Mitsuya
Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.
March 2023, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!