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. 2016 Oct 1;26(19):4748-4752.
doi: 10.1016/j.bmcl.2016.08.037. Epub 2016 Aug 13.

Indole-based allosteric inhibitors of HIV-1 integrase

Pratiq A Patel  1 , Nina Kvaratskhelia  2 , Yara Mansour  3 , Janet Antwi  4 , Lei Feng  2 , Pratibha Koneru  2 , Mathew J Kobe  2 , Nivedita Jena  4 , Guqin Shi  4 , Mosaad S Mohamed  5 , Chenglong Li  4 , Jacques J Kessl  6 , James R Fuchs  7
Affiliations

Indole-based allosteric inhibitors of HIV-1 integrase

Pratiq A Patel et al. Bioorg Med Chem Lett. .

Abstract

Employing a scaffold hopping approach, a series of allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) have been synthesized based on an indole scaffold. These compounds incorporate the key elements utilized in quinoline-based ALLINIs for binding to the IN dimer interface at the principal LEDGF/p75 binding pocket. The most potent of these compounds displayed good activity in the LEDGF/p75 dependent integration assay (IC50=4.5μM) and, as predicted based on the geometry of the five- versus six-membered ring, retained activity against the A128T IN mutant that confers resistance to many quinoline-based ALLINIs.

Keywords: ALLINI; HIV integrase inhibitor; Scaffold hopping.

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Figures

Figure 1
Figure 1
A docking model overlay of BI-1001 (purple) and an indole analogue (white) in the LEDGF/p75 binding pocket to HIV-1 IN dimer interface. Individual IN subunits are shown in green and blue.
Figure 2
Figure 2
Dose response curves for 5c promoting aberrant multimerization of WT (black squares) and A128T (red circles) INs. Error bars indicate SD from three independent experiments. IC50 values for wild type and A128T INs were 16.1 ± 2.0 μM and 16.0 ± 1.4 μM, respectively.
Figure 3
Figure 3
The structural orientation of compound 5c bound to the HIV1 Integrase CCD dimer in the presence and absence of the resistance A128T mutation. (A) The crystal structure of 5c in complex with CCD (PDB ID: 5KGW). The two CCD subunits are colored cyan and green with the electrostatic interaction and hydrogen bonds represented as black dashes. (B) Comparison of BI-1001 (PDB ID: 4DMN) and 5c binding to the CCD. (C) The binding of 5c is unchanged when comparing the overlay of 5KGW with the crystal structure of 5c bound to CCD containing the A128T substitution (PDB ID: 5KGX). The subunits of 5KGX are colored yellow and grey with 5c also colored in yellow.
Scheme 1
Scheme 1
Method for preparation of indole analogues 5a-5e.
Scheme 2
Scheme 2
Synthesis of the homologated acid 10.
Scheme 3
Scheme 3
Functional inversion of indole leading to the preparation of 15.
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