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. 2023 Mar 7;24(6):5101.
doi: 10.3390/ijms24065101.

Microwave-Assisted Synthesis of 3-Hydroxy-2-oxindoles and Pilot Evaluation of Their Antiglaucomic Activity

Alexander M Efremov  1   2 , Olga V Beznos  3 , Roman O Eremeev  1 , Natalia B Chesnokova  3 , Elena R Milaeva  1   2 , Elena F Shevtsova  2 , Natalia A Lozinskaya  1
Affiliations

Microwave-Assisted Synthesis of 3-Hydroxy-2-oxindoles and Pilot Evaluation of Their Antiglaucomic Activity

Alexander M Efremov et al. Int J Mol Sci. .

Abstract

Glaucoma is a widespread neurodegenerative disease for which increased intraocular pressure (IOP) is a primary modifiable risk factor. Recently, we have observed that compounds with oxindole scaffolds are involved in the regulation of intraocular pressure and therefore have potential antiglaucomic activity. In this article, we present an efficient method for obtaining novel 2-oxindole derivatives via microwave-assisted (MW) decarboxylative condensation of substituted isatins with malonic and cyanoacetic acids. Various 3-hydroxy-2-oxindoles were synthesized using MW activation for 5-10 min with high yields (up to 98%). The influence of novel compounds applied in instillations on IOP was studied in vivo on normotensive rabbits. The lead compound was found to reduce the IOP by 5.6 Torr (ΔIOP for the widely used antiglaucomatousic drug timolol 3.5 Torr and for melatonin 2.7 Torr).

Keywords: glaucoma; intraocular pressure; isatin; microwave irradiation; oxindole.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Condensation of isatins with malonic and cyanoacetic acids in different conditions.
Scheme 2
Scheme 2
Proposed mechanism A for condensation of isatins with cyanoacetic acid.
Scheme 3
Scheme 3
Proposed mechanism B for condensation of isatins with malonic acid.
Figure 1
Figure 1
Comparison of the 1H NMR characteristic signals of compounds 2a,b,d,f,e.
Figure 2
Figure 2
Graphical representation of IOP reduction after instillation of 50 µL of 0.1%w/v solution of some oxindole compounds. Timolol and melatonin were used as reference compounds. All data were obtained using 5 animals (10 eyes). One-way ANOVA and Dunn test: **—p ≤ 0.01 in comparison with melatonin; #—p ≤ 0.05 in comparison with timolol.
Figure 3
Figure 3
Duration of IOP decreases after the instillation (50 µL of 0.1%w/v solution per eye) of most active compounds 2. Timolol and melatonin were used as references. All data were obtained using 5 animals (10 eyes) and presented as mean ± SEM. For the «5 h» point—one-way ANOVA and Dunn test: *—p ≤ 0.05, **—p ≤ 0.01 in comparison with melatonin; #—p ≤ 0.05 in comparison with timolol.
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