Application of the Morita-Baylis-Hillman reaction in the synthesis of 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones as potential HIV-1 integrase inhibitors

Khethobole C Sekgota; Swarup Majumder; Michelle Isaacs; Dumisani Mnkandhla; Heinrich C Hoppe; Setshaba D Khanye; Frederik H Kriel; Judy Coates; Perry T Kaye

doi:10.1016/j.bioorg.2017.09.015

Application of the Morita-Baylis-Hillman reaction in the synthesis of 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones as potential HIV-1 integrase inhibitors

Bioorg Chem. 2017 Dec:75:310-316. doi: 10.1016/j.bioorg.2017.09.015. Epub 2017 Sep 22.

Authors

Khethobole C Sekgota¹, Swarup Majumder¹, Michelle Isaacs², Dumisani Mnkandhla², Heinrich C Hoppe³, Setshaba D Khanye⁴, Frederik H Kriel⁵, Judy Coates⁵, Perry T Kaye⁶

Affiliations

¹ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa.
² Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
³ Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
⁴ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
⁵ Centre for Metal-based Drug Discovery, Advanced Materials Division, Mintek, Randburg 2125, South Africa.
⁶ Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa; Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa. Electronic address: [email protected].

PMID: 29080495
DOI: 10.1016/j.bioorg.2017.09.015

Abstract

A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.

Keywords: 2-quinolones; Bioassay; HIV-1 integrase inhibitors; Morita_Baylis-Hillman; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Survival / drug effects
Enzyme Activation / drug effects
HEK293 Cells
HIV Integrase / chemistry*
HIV Integrase / metabolism
HIV Integrase Inhibitors / chemical synthesis*
HIV Integrase Inhibitors / metabolism
HIV Integrase Inhibitors / pharmacology
HIV Reverse Transcriptase / antagonists & inhibitors
HIV Reverse Transcriptase / metabolism
HIV-1 / enzymology*
Humans
Quinolones / chemistry*
Quinolones / metabolism
Quinolones / pharmacology
Structure-Activity Relationship

Substances

HIV Integrase Inhibitors
Quinolones
HIV Integrase
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase