Compounds acting against HIV: Imidazo[1,2-a]pyridines as non-nucleoside reverse transcriptase inhibitors (NNRTIs)

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Compounds acting against HIV

Imidazo[1,2-a]pyridines as non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Moira Bode, Igle Gledhill, David Gravestock, Heinrich Hoppe, Tasmiyah Khan,

Simon Moleele, Lindiwe Nkabinde, Stephen Pelly, Chris van der Westhuyzen

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HIV drug targets

Viral enzymes:

•Reverse Transcriptase

•Protease

•Integrase

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Courtesy Howard Hughes medical centre

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Two types of inhibitors:

NRTIs and NNRTIs

Reverse Transcriptase

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NRTI

NNRTI

Inhibitor Modes of action

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NNRTIs in HIV treatment

• Non-competitive allosteric inhibitors of reverse transcriptase

• Form part of first-line treatment regimen of HAART, eg.

nevirapine, efavirenz

• Potent, highly selective anti-HIV agents

• Structurally diverse

• Generally good safety profile

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Slide 8

N N

NH

Res Act = 41%

IC 50 = 29 uM (RT) IC 50 = 41 uM (PBMC)

Prepared by the Groebke multi-component coupling reaction

Hit compound identified from an enzymatic RT screen – poorly active in whole cell anti-HIV assay

N N

R 2 NHR 3 N

NH 2

+ R 2 CHO + R 3 N C

R 1 R 1

2 5 3

6 7

8

Imidazo[1,2-a]pyridines

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Reverse transcriptase assay

Compounds showing < 20% residual activity in enzymatic assay

were submitted to SRI for whole-cell anti-HIV infectivity assay

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Slide 10

N N

R 2 NH R 3

R 1 alkyl

branched alkyl cycloalkyl

phenyl

halogenated phenyl

alkyl

branched alkyl cycloalkyl

aromatic H

halogen methyl cyano alkoxy

Hit to Lead Development

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N N

R 2 NHR 3 R 1

N N

NH

Res Act = 75%

N N

NH HO

Res Act = 87%

N N

NH Cl

Res Act = 7%

N N

NH

Res Act = 76%

N N

NH

Res Act = 55%

N N

NH

Res Act = 96%

N N

NH

Cl Res Act = 77%

N N

NH

Res Act = 22%

N N

NH

Res Act = 70%

N N

NH Cl

Res Act = 73%

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N N

NH Cl

Lead compound identified

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Lead optimisation

N N

N H C l

Res Act = 18%

I C

5 0

= 7 µM MAGI IC

₅₀

= 3 µM

N N

N H C l

Res Act = 11%

IC

50

= 5 µM MAGI IC

₅₀

= 0.6 µM

N N

N H C l

Res Act = 3%

IC

₅₀

= 2 µM MAGI IC

₅₀

= 0.2 µM

N N

NH Cl

Res Act = 5%

I C

5 0

= 3.5 µM MAGI I C

5 0

= 0. 18 µM

N N

N H C l

Res Act = 13%

IC

50

= 8 µM MAGI IC

50

= 0.6 µM

N N

Cl N H

C l

Res Act = 4%

IC

50

= 1.5 µM MAGI IC

₅₀

= 0.18 µM

N N

N H C l

NC

Res Act = 12%

IC

₅₀

= 7 µM MAGI IC

50

< 0.6 µM

N N

NH Cl

C l

Res Act = 20%

IC

₅₀

= 15 µM MAGI IC

50

= 0.8 µM

N N

N H C l

Res Act = 57%

C N N

N

NH Cl

Res Act = 94%

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Summary: Activity improvement

N N

NH

N N

NH Cl

N N

NH Cl

CN

IC

₅₀

= 4.4 uM (RT) IC

₅₀

= 0.16 uM (PBMC) IC

₅₀

= 0.41 uM (MAGI) cf . Nevirapine

IC

₅₀

=0.67 uM (RT) IC

₅₀

=0.033 uM (P BMC) IC

₅₀

= 29 uM (RT)

IC

₅₀

= 41 uM (PBMC) cf . Nevirapine

IC

₅₀

= 0.67 uM (RT) IC

₅₀

= 0.033 uM ( PBM C)

IC

₅₀

= 3.5 uM (RT) IC

₅₀

= 0.18uM (MAGI) cf . Nevirapine

IC

₅₀

= 0.67uM (RT)

IC

₅₀

= 0.10 uM (M AGI)

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Slide 16

Conclusions

• A compound possessing anti-HIV activity similar to that of FDA-approved nevirapine was developed

• Acts as a non-nucleoside reverse transcriptase inhibitor

• Compound shows good cell permeability

• Quantitative structure activity relationship (QSAR) developed for the compound series