New spirothiazolidinone derivatives: Synthesis and antiviral evaluation

Abstract

A new series of N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives were designed, synthesized, and evaluated for their antiviral activity. These new spirothiazolidinone compounds (3a-f, 4a-f) were prepared by a cyclocondensation reaction of hydrazides (1, 2) and appropriate ketones with 2-sulfanylpropionic acid. All compounds were characterized by IR, 1 H NMR, and elemental analysis. N-(8-Ethyl-2-methyl-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)-4-methylbenzamide (3c) and 4-methyl-N-(2-methyl-3-oxo-8-propyl-1-thia-4-azaspiro[4.5]decan-4-yl)benzamide (3d) exhibited strong activity against influenza A/H3N2 virus, at EC 50 values of 0.5 and 0.2 mM and a selectivity index of about 50. Besides, 4-methyl-N-(2-methyl-3-oxo-8-phenyl-1-thia-4-azaspiro[4.5]decan-4yl)benzamide (3e) and 2-(4-chlorophenoxy)-N-(3-oxo-8-tert-butyl-1-thia-4-azaspiro[4.5]dec-4-yl)acetamide (4f) inhibited human coronavirus 229E, at EC 50 values of 9.8 and 8.6 mM, and a favorable selectivity index for 4f. This indicates the versatility of the spirothiazolidinone scaffold to achieve new classes of antiviral molecules.

A review on advances in synthetic methodology and biological profile of spirothiazolidin‐4‐ones

“…Antiviral activity of compounds 63 against influenza A and B viruses and human coronaviruses 229E strain was published by Apaydın et al [48]. 63a and 63b have shown satisfactory inhibition of influenza A/H 3 N 2 (EC 50 = 1.4, 0.80).…”

“…Apaydın et al [48] reported the preparation of a novel azaspiro-carboxamides 63 and 65. The hydrazines 62 and 64 were refluxed with appropriate cyclohexanone 44 and S C H E M E 1 2 Synthesis of novel bis-pyrimidinyl-spiro-4-thiazolidinones 2-sulfanylpropanoic acid 3 in toluene to furnish corresponding spirothiazolidinones (Scheme 16).…”

Synthesis of new N‐(3‐oxo‐1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)pyridine‐3‐carboxamide derivatives and evaluation of their anti‐influenza virus and antitubercular activities

“…[ 8 ] For the lead compound, A1 , the average EC 50 for different strains of human influenza A/H3N2 was 9.6 µM and the IC 50 (cytostatic activity) was 93 µM, yielding a selectivity index of 10. Subsequent structure–activity relationship (SAR) analyses demonstrated that antiviral efficacy and selectivity show no drastic change when the aromatic part is replaced by 1‐adamantyl ( A2 ), [ 9 ] 5‐chloro‐2‐hydroxy/methoxyphenyl ( A3 ), [ 10,11 ] 4‐chlorophenoxymethyl ( A4 ), [ 12 ] or 2‐methylfuran‐3‐yl ( A5 ) [ 13 ] (Figure 1). The compounds were proven to act as influenza A/H3N2 virus fusion inhibitors by hindering the conformational change of the viral hemagglutinin (HA) at low pH, a process required to provoke the fusion of the viral envelope and endosomal membrane.…”