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. 2019 May 6;10(6):970-973.
doi: 10.1039/c9md00178f. eCollection 2019 Jun 1.

Discovery of (aza)indole derivatives as novel respiratory syncytial virus fusion inhibitors

Xiufang Zheng  1 , Chungen Liang  1 , Lisha Wang  1 , Kun Miao  1 , Baoxia Wang  1 , Weixing Zhang  1 , Dongdong Chen  1 , Guolong Wu  1 , Wei Zhu  1 , Lei Guo  1 , Song Feng  1 , Lu Gao  1 , Hong C Shen  1 , Hongying Yun  1
Affiliations

Discovery of (aza)indole derivatives as novel respiratory syncytial virus fusion inhibitors

Xiufang Zheng et al. Medchemcomm. .

Abstract

A new class of indole derivatives (3) have been identified as potent RSV fusion inhibitors. SAR exploration revealed that 5-Cl and the sulfonyl side chain of the indole scaffold are crucial for anti-RSV activity. Further optimization led to the discovery of a cyclic sulfone (8i) with 2 nM anti-RSV activity and a much improved PK profile compared to the non-cyclic sulfone counterpart.

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Figures

Fig. 1
Fig. 1. Structures of selected RSV inhibitors.
Scheme 1
Scheme 1. Synthesis of spirooxindole derivatives 3. Reagents and conditions: (a) i. R2–X or R2–OTs, K2CO3, CH3CN, heat; ii. LiAlH4, THF, 0 °C; (b) i. LiAlH4, THF, 0 °C; ii. CH2CHSO2R, Cs2CO3, DMF, heat; (c) i. MsCl, Et3N, DCM, 0 °C; ii. 6, NaH, DMF, 0 °C; (d) 6, PPh3, DIAD, THF, rt.
Fig. 2
Fig. 2. 8i inhibited RSV F protein-induced fusion process. The F gene of RSV Long strain was codon-optimized and synthesized by GenScript. The full length of the F gene was cloned into the pcDNA5 TOPO TA vector (Invitrogen). Then RSV-F stable cell lines were generated by co-transfection of the RSV-F-pcDNA5 and pOG44 plasmids into the Flp-In T-REx 293 cell line (Invitrogen) and 100 μg ml–1 hygromycin B was used to select stable transfectants. RSV-F expression was induced by 1 μg ml–1 tetracycline. The compound was serially diluted and added into the RSV-F expressing cells. The cell–cell fusion was observed by microscopy three days after the compound addition. The cell fusion induced by the RSV fusion protein was marked with a red circle.
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References

    1. Borchers A. T., chang C., Gershwin M. E., Gershwin L. J. Clin. Rev. Allergy Immunol. 2013;45:331–379. - PMC - PubMed
    1. Greenough A. Curr. Opin. Pulm. Med. 2002;8:214–217. - PubMed
    2. Piedimonte G., Perez M. K. Curr. Opin. Pharmacol. 2014;16:82–88. - PMC - PubMed
    3. Cox R., Plemper R. K. Expert Opin. Drug Discovery. 2016;11:543–556. - PMC - PubMed
    1. Dudas R. A., Karron R. A. Clin. Microbiol. Rev. 1998;11:430–439. - PMC - PubMed
    2. Neuzil K. M. Clin. Vaccine Immunol. 2016;23:186–188. - PMC - PubMed
    1. Heylen E., Neyts J., Jochmans D. Biochem. Pharmacol. 2017;127:1–12. - PubMed
    2. Ventre K., Randolph A. G. Cochrane Database Syst. Rev. 2010:CD000181. doi: 10.1002/14651858. - DOI - PMC - PubMed
    3. The IMpact-RSV Study Group Pediatrics. 1998;102:531–537. - PubMed
    1. Ding W. D., Mitsner B., Krishnamurthy G., Aulabaugh A., Hess C. D., Zaccardi J., Cutler M., Feld B., Gazumyan A., Raifeld Y., Antonia Nikitenko A., Lang S. A., Gluzman Y., O'Hara B., Ellestad G. A. J. Med. Chem. 1998;41:2671–2675. - PubMed
    2. Andries K., Moeremans M., Gevers T., Willebrords R., Sommen C., Lacrampe J., Janssens F., Wyde P. R. Antiviral Res. 2003;60:209–219. - PubMed
    3. Bonfanti J. F., Meyer C., Doublet F., Fortin J., Muller P., Queguiner L., Gevers T., Janssens P., Szel H., Willebrords R., Timmerman P., Wuyts K., van Remoortere P., Janssens F., Wigerinck P., Andries K. J. Med. Chem. 2008;51:875–896. - PubMed
    4. Yu K. L., Sin N., Civiello R. L., Wang X. A., Combrink K. D., Gulgeze H. B. Bioorg. Med. Chem. Lett. 2007;17:895. - PubMed
    5. Sun Z., Pan Y., Jiang S., Lu L. Viruses. 2013;5:211–225. - PMC - PubMed
    6. Mackman R. L., Sangi M., Sperandio D., Parrish J. P., Eisenberg E., Perron M. J. Med. Chem. 2015;58:1630–1643. - PubMed
    7. ClinicalTrials.gov Identifier: NCT01756482.
    8. Roymans D., Alnajjar S. S., Battles M. B., Sitthicharoenchai P., Furmanova-Hollenstein P., Rigaux P., Berg J. V. D., Kwanten L., Ginderen M. V., Verheyen N., Vranckx L., Jaensch S., Arnoult E., Voorzaat R., Gallup J. M., Larios-Mora A., Crabbe M., Huntjens D., Raboisson P., Langedijk J. P., Ackermann M. R., McLellan J. S., Vendeville S., Koul A. Nat. Commun. 2017;8:167. - PMC - PubMed
    9. Cockerill G. S., Good J. A. D., Mathews N. J. Med. Chem. 2019;62:3206–3227. - PubMed