Abstract

Novel compounds 1a–u, which can be considered as hybrid analogues of MKC-442 and pyridinon, have been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (HIV-1 RT). Starting from 6-methyuracil 2, 1-alkylated-5-bromomethyl-6-methyluracils 8 was prepared in four steps by hydroxylmethylation, etherification, N-1 alkylation, and bromination. Finally, compounds 1a–u were achieved in the displacement of 5-bromomethyl group by nucleophiles with amino compounds. Some of compounds 1a–u showed potent inhibitory activity against HIV-1 RT. The most active compounds showed activity in the low micromolecular range with IC₅₀ values (IC₅₀ 0.82–5.09 μM) comparable to that of nevirapine (IC₅₀ 10.60 μM). The biological testing results are in accordance with the docking.

Graphical abstract

A synthesis route to get a novel series of hydrid analogues of MKC-442 and pyridinon as inhibitors of HIV-1 reverse transcripts and evaluate results about their potent inhibiting activity against HIV-RT.

Full-size image (7K)

Keywords: HIV-1 reverse transcriptase; Non-nucleoside reverse ranscriptase inhibitors (NNRTIs); HEPT analogues

Article Outline

1. Introduction

2. Results and discussions

2.1. Design of target molecule

2.2. Chemistry

2.3. Biological activity

2.4. Conclusions

3. Experimental

3.1. 5-Hydroxymethyl-6-methyluracil (3)

3.2. 5-Benzyloxymethyl-6-methyluracil (6)

3.3. 1-(Ethoxymethyl)-5-(benzyloxymethyl)-6-methyluracil (7a)

3.4. 1-(Benzyloxymethyl)-5-(benzyloxymethyl)-6-methyluracil (7b)

3.5. 1-(Ethoxymethyl)-5-(bromomethyl)-6-methyluracil (8a)

3.6. 1-(Benzyloxymethyl)-5-(bromomethyl)-6-methyluracil (8b)

3.7. General procedure for the synthesis of 1a–1m

3.7.1. 1-(Ethoxymethyl)-5-[(2,4,5-trichloro-phenylamino)-methyl]-6-methyluracil (1a)

3.7.2. 1-(Ethoxymethyl)-5-(p-tolylamino-methyl)-6-methyluracil (1b)

3.7.3. 1-(Ethoxymethyl)-5-[(4-nitro-phenylamino)-methyl]-6-methyluracil (1c)

3.7.4. 1-(Ethoxymethyl)-5-[(2-nitro-phenylamino)-methyl]-6-methyluracil (1d)

3.7.5. 1-(Ethoxymethyl)-5-[(3-nitro-phenylamino)-methyl]-6-methyluracil (1e)

3.7.6. 1-(Ethoxymethyl)-5-(cyclohexylaminomethyl)-6-methyluracil (1f)

3.7.7. 1-(Ethoxymethyl)-5-[(methyl-phenylamino)-methyl]-6-methyluracil (1g)

3.7.8. 1-(Ethoxymethyl)-5-[(2,5-dimethyl-phenylamino)-methyl]-6-methyluracil (1h)

3.7.9. 1-(Ethoxymethyl)-5-[(2,6-dimethyl-phenylamino)-methyl]-6-methyluracil (1i)

3.7.10. 1-(Ethoxymethyl)-5-[(2,4,6-trichloro-phenylamino)-methyl]-6-methyluracil (1j)

3.7.11. 1-(Ethoxymethyl)-5-(pyridin-2-ylaminomethyl)-6-methyluracil (1k)

3.7.12. 1-(Ethoxymethyl)-5-(pyrimidin-2-ylaminomethyl)-6-methyluracil (1l)

3.7.13. 1-(Ethoxymethyl)-5-(naphthalen-1-ylaminometh-yl)-6-methyluracil (1m)

3.8. General procedure for the synthesis of 1n–1u

3.8.1. 1-(Benzyloxymethyl)-5-[(methyl-phenylamino)-methyl]-6-methyluracil (1n)

3.8.2. 1-(Benzyloxymethyl)-5-(p-tolylamino-methyl)-6-methyluracil (1o)

3.8.3. 1-(Benzyloxymethyl)-5-[(4-nitro-phenylamino)-methyl]-6-methyluracil (1p)

3.8.4. 1-(Benzyloxymethyl)-5-[(2-nitro-phenylamino)-methyl]-6-methyluracil (1q)

3.8.5. 1-(Benzyloxymethyl)-5-[(3-nitro-phenylamino)-methyl]-6-methyluracil (1r)

3.8.6. 1-(Benzyloxymethyl)-5-[(2,4,5-trichloro-phenylamino)-methyl]-6-methyluracil (1s)

3.8.7. 1-(Benzyloxymethyl)-5-(cyclohexylaminomethyl)-6-methyluracil (1t)

3.8.8. 1-(Benzyloxymethyl)-5-[(2,4,6-trichloro-phenylamino)-methyl]-6-methyluracil (1u)

Acknowledgements

References