Arylazolyl(azinyl)thioacetanilides. Part 16: Structure-based bioisosterism design, synthesis and biological evaluation of novel pyrimidinylthioacetanilides as potent HIV-1 inhibitors

doi:10.1016/j.bmc.2014.08.001

Bioorganic & Medicinal Chemistry

Volume 22, Issue 19, 1 October 2014, Pages 5290-5297

https://doi.org/10.1016/j.bmc.2014.08.001 Get rights and content

Abstract

A series of novel pyrimidinylthioacetanilides were designed, synthesized, and evaluated for their biological activity as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Most of the tested compounds were proved to be effective in inhibiting HIV-1 (IIIB) replication with EC₅₀ ranging from 0.15 μM to 24.2 μM, thereinto compound 15 was the most active lead with favorable inhibitory activity against HIV-1 (IIIB) (EC₅₀ = 0.15 μM, SI = 684). Besides, compound 6 displayed moderate inhibition against the double-mutated HIV-1 strain (K103N/Y181C) (EC₅₀ = 3.9 μM). Preliminary structure–activity relationships (SARs), structure–cytotoxicity relationships (SCRs) data, and molecular modeling studies were discussed as well, which may provide valuable insights for further optimizations.

Graphical abstract

A novel series of non-nucleoside reverse transcriptase inhibitors with pyrimidinylthioacetanilide scaffold was rationally designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells.

Introduction

The reverse transcriptase (RT) enzyme of human immunodeficiency virus type 1 (HIV-1) has always been an attractive target for exploration of highly effective and low toxic anti-HIV drugs due to its specificity and crucial role in replication process.¹ Especially non-nucleoside RT inhibitors (NNRTIs), as key components of highly active antiretroviral therapy (HAART), have gained a definitive and indispensable place in first-line drug regimens.² However, the effectiveness of clinical used NNRTIs can be hampered by a high genetic barrier to resistance and severe side effects in the long-term administration. As a consequence, further optimization of additional drugs and improved efficacy of long-term HIV treatment are still urgently needed.3, 4, 5

Among the structurally diverse HIV-1 NNRTIs, arylazolylthioacetanilides (AATAs) was identified as one of the most prominent of these promising families because of the excellent activities against wild-type (WT) viruses and the most common resistant strains such as K103N and/or Y181C mutation.6, 7, 8, 9, 10, 11, 12 VRX-480733 and RDEA-806, two 1,2,4-triazolythioacetanilide derivatives, have been chosen as candidates for further studies. Particularly RDEA806, developed by Ardea Biosciences, with a high barrier to resistance against the common mutations that develop with efavirenz and nevirapine, was once entered phase IIa clinical trials (in 2008) (Fig. 1).2, 11

Prompted by these promising results, we have previously done some relatively comprehensive exploration on the discovery of AATAs derivatives as potent HIV-1 inhibitors guiding by structure-based bioisosterism principle. In recent years, the surprising initial findings coming out of our ongoing investigations was that replacement of the five-membered azoles moiety by an array of six-membered heteroaromatic bioisosteres (such as pyrazine, pyridazine and 1,2,4-triazine), led to the identification of additional series of arylazinylthioacetanilides that possessed potent anti-HIV activities in cell culture assay (Fig. 2).¹³ Moreover, it is becoming increasingly clear that there were significant differences in the electronic and conformational contribution of the heterocyclic groups to the binding of the inhibitors with the HIV-1 RT.12, 13 Therefore, it is likely that other six-membered heterocycles with synthetic accessibility and drug-like properties are also acceptable isosteric replacements for the center ring in the existing compounds.

Herein, in order to further explore the diverse chemical space and the structure–activity relationships (SARs) of arylazinylthioacetanilides, a novel series of pyrimidin-4-ylthioacetanilides were designed via structure-based bioisosterism principle, synthesized by a facile synthetic route and evaluated for their activities as HIV-1 NNRTIs. Notably, in the newly designed analogues, different substituents, varying in size and electronic nature, were introduced in the phenyl ring of the anilide moiety which is located at the protein-solvent interface region of RT, to further investigate potential interaction. Furthermore, a 1,2,3-triazole motif was tentatively employed to replace the original acetamide linker (Fig. 2). Their anti-HIV activities, preliminary SARs, structure–cytotoxicity relationships (SCRs) and molecular modeling results were discussed in detail.

Section snippets

Chemistry

To obtain the desired compounds 6–21, the synthetic steps adopted were straightforwardly outlined in Scheme 1. The key intermediate 5-(naphthalen-1-yl)pyrimidin-4-ol (3) was prepared from commercially available 5-bromopyrimidin-4-ol (1) and naphthalen-1-ylboronic acid (2) through the widely utilized Suzuki reaction.14, 15 Treatment of (3) with phosphorus pentasulfide in pyridine under reflux afforded 5-(naphthalen-1-yl)pyrimidine-4-thiol (4).16, 17 The target compounds

Conclusion

In summary, in the present work, a series of novel pyrimidinylthioacetanilides were designed, synthesized, and evaluated for their biological activities as potent NNRTIs, which is an extension of our unremitting efforts toward discovery of new molecular entities with anti-HIV activity. Most of these compounds were proved to be effective in inhibiting HIV-1 replication, thereinto 15 was the most active lead with favorable inhibitory activity against HIV-1 IIIB (EC₅₀ = 0.15 μM). Besides, compound 6

Synthetic procedures and analytical data

Mass spectrometry was performed on an API 4000 triple-quadrupole mass spectrometer (Applied Biosystems/MDS Sciex, Concord, ON, Canada). ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AV-400 spectrometer (Bruker BioSpin, Switzerland), using solvents as indicated (DMSO-d₆). Chemical shifts were reported in δ values (ppm) with tetramethylsilane as the internal reference, and J values were reported in hertz (Hz). Melting points (mp) were determined on a micromelting point apparatus (Tian Jin

Acknowledgments

We thank K. Erven, K. Uyttersprot and C. Heens for technical assistance with the HIV assays. The financial support from the National Natural Science Foundation of China (NSFC No. 81273354, No. 81102320), Key Project of NSFC for International Cooperation in China (No. 30910103908), Research Fund for the Doctoral Program of Higher Education of China (Nos. 20110131130005, 20110131120037), The Natural Science Foundation of Shandong Province, China (No. ZR2009CM016).

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^☆: Part 1–12: Reference 12; Part 13–15: Reference 13.

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Arylazolyl(azinyl)thioacetanilides. Part 16: Structure-based bioisosterism design, synthesis and biological evaluation of novel pyrimidinylthioacetanilides as potent HIV-1 inhibitors☆

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

Synthetic procedures and analytical data

Acknowledgments

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Antimicrob. Agents Chemother.

Eur. J. Org. Chem.

Eur. J. Med. Chem.

Nat. Protoc.

Science

Biochemistry

J. Med. Chem.