Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues

Abstract

A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9μM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45-58μM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45-73μM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1-19μM range.

Keywords: Antiviral; Cytostatic; Isoxazolidines; Naphthalimides; Phosphonates.

Graphical abstract

Figure 1

Structures of known intercalators.

Figure 2

Biologically active isoxazolidines.

Scheme 1

Retrosynthesis of (isoxazolidinyl)phosphonates 9 and 10.

Scheme 2

Reaction conditions: (a) H₂SO₄, HNO₃; (b) SnCl₂, HCl; (c) R′NH₂, EtOH, see Table 1; (d) acryloyl chloride, NEt₃, see Table 1; (e) allylamine, EtOH; (f) Ac₂O.

Scheme 3

Reaction conditions: toluene or toluene–chloroform, 70 °C.

Scheme 4

Reaction conditions: toluene or toluene–chloroform, 70 °C.

Figure 3

The ₃E conformation of an isoxazolidine ring in trans-9a–f.