Novel <i>N</i>‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)carboxamide derivatives as potent and selective influenza virus fusion inhibitors

Göktaş, Füsun; Özbi̇l, Mehmet; Cesur, Nesrin; Vanderlinden, Evelien; Naesens, Lieve; Cesur, Zafer

doi:10.1002/ardp.201900028

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…The favorable effect of the ethyl (3c) and propyl (3d) substituents on position 8 of the spirocyclic system fits with our previous SAR observations. [16][17][18][19][20] Regarding the aromatic part, we now show that the 4-methylphenyl moiety (Series 3) is clearly superior to the 4-chlorophenoxy moiety (Series 4). A distinct SAR was observed for the human coronavirus 229E strain, evaluated in human HEL cells ( Table 2).…”

Section: Biological Activitymentioning

confidence: 57%

“…[16] Mechanistic work showed that these molecules inhibit HA-mediated membrane fusion, by preventing the HA refolding process that occurs after the virus has entered the host cell by endocytosis. [16] We conducted intensive research on the structure-activity relationship of these spirothiazolidinones [17][18][19] and, recently, achieved analogues with nanomolar antiinfluenza virus activity, by introducing a moiety that supposedly leads to endosomal accumulation of the compound. [20] In another study, we observed that some of these spirothiazolidinone-bearing analogues exhibit promising anti-CoV activity, [21] the mechanism of which is currently being investigated.…”

Section: Introductionmentioning

confidence: 99%

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New spirothiazolidinone derivatives: Synthesis and antiviral evaluation

Apaydın

Loy

Stevaert

et al. 2020

Phosphorus, Sulfur, and Silicon and the Related Elements

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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.

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Section: Biological Activitymentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

New spirothiazolidinone derivatives: Synthesis and antiviral evaluation

Apaydın

Loy

Stevaert

et al. 2020

Phosphorus, Sulfur, and Silicon and the Related Elements

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“…a new class of N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)carboxamide compounds containing a 5‐chloro‐2‐methoxy benzamide moiety have been discovered. To possibly develop broader‐acting influenza A virus fusion inhibitors, further investigation against a wider variety of influenza A viruses (including more recent A/H3 N2 strains) identified compounds 59 and 60 (Figure 24) with promising antiviral activity [45] …”

Section: Anti‐influenza Small Moleculementioning

confidence: 99%

“…[44] According to Goktas inhibitors, further investigation against a wider variety of influenza A viruses (including more recent A/H3 N2 strains) identified compounds 59 and 60 (Figure 24) with promising antiviral activity. [45] A natural substance with widespread antiviral entry activity called oleanolic acid (OA) and three more analogs, echinocystic acid (EA), ursolic acid (UA), and betulinic acid, were conjugated with sialic acid by Xu Han et al In the MDCK cell culture, the antiviral activity against the influenza A/WSN/33 (H1 N1) virus was tested on a total of twenty-four conjugated sialic acid and penta cyclic triterpene derivatives with various linkers. The IC 50 value for the most active compound 61 (Figure 25) was 41.2 μM.…”

Section: Anti-influenza Small Moleculementioning

confidence: 99%

Recent Efforts in Identification of Privileged Scaffolds as Antiviral Agents

Yadav,

Singh,

Sharma

et al. 2023

Chemistry & Biodiversity

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Viral infections are the most important health concern nowdays to mankind, which is unexpectedly increasing the health complications and fatality rate worldwide. The recent viral infection outbreak develops a pressing need for small molecules that can be quickly deployed for the control/treatment of re‐emerging or new emerging viral infections. Numerous viruses, including the human immunodeficiency virus (HIV), hepatitis, influenza, SARS‐CoV‐1, SARS‐CoV‐2, and others are still challanging due to emerging resistant to known drugs. Therefore, there is alway a need to search for new antiviral small molecules who can combat viral infection with new mode of action. This review highlighted rececnt progress on development of new antiviral molecule based on natural product inspired scafflods. Herein, structure activity relationship of the FDA approved drugs alongwith the molecular docking studies of selected compounds have been discussed against several target proteins. The findings of new small molecules as neuraminidase inhibtors, other than known drug scafflods, Anti‐HIV and SARS‐CoV are incorporated in this review paper.

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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

Cihan-Üstündağ

Acar

Naesens

et al. 2022

Archiv der Pharmazie

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We here report the synthesis, structural characterization, and evaluation of the antiviral and antitubercular activities of a novel series of hybrid spirothiazolidinone derivatives (2a–f and 3a–f) containing the nicotinohydrazide moiety, which is an isomer form of the approved antitubercular drug isoniazid. When evaluated for activity against influenza A/H1N1, A/H3N2, and B viruses, three of the new compounds proved to possess specific antiviral activity against the influenza A/H3N2 virus. The most active analog 3a, bearing a 2,8‐dimethyl group at the spiro ring, displayed an antiviral EC50 value of 5.2 µM. Compound 3a produced no cytotoxicity at 100 µM, the highest concentration tested, giving a selectivity index of at least 19. Structure–activity relationship analysis indicated that the absence of the methyl substituent at the 2‐position and the presence of a bulky substituent at the 8‐position of the spirothiazolidinone system caused a significant decrease in antiviral activity. The in vitro antitubercular activity of compounds 2a–f and 3a–f was determined for six different drug‐sensitive/drug‐resistant laboratory strains and clinical isolates of Mycobacterium tuberculosis. Compounds 2c, 2d, 3b, 3c, and 3d showed weak antitubercular activity against different strains, with MIC values of 125–250 μM.

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Novel N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)carboxamide derivatives as potent and selective influenza virus fusion inhibitors

Cited by 5 publications

References 31 publications

New spirothiazolidinone derivatives: Synthesis and antiviral evaluation

New spirothiazolidinone derivatives: Synthesis and antiviral evaluation

Recent Efforts in Identification of Privileged Scaffolds as Antiviral Agents

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

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