Improved Synthesis of Effective 3-(Indolin-6-yl)-4-(N-pyrazole-sulfonamide)-1H-pyrrolo[2,3-b]pyridine-Based Inhibitors of NADPH Oxidase 2

Improved Synthesis of Effective 3-(Indolin-6-yl)-4-(N-pyrazole-sulfonamide)-1H-pyrrolo[2,3-b]pyridine-Based Inhibitors of NADPH Oxidase 2 Full article

Journal

International Journal of Molecular Sciences
ISSN: 1661-6596 , E-ISSN: 1422-0067

Output data

Year: 2025, Volume: 26, Number: 8, Article number : 3647, Pages count : DOI: 10.3390/ijms26083647

Authors

Potapov Konstantin V. ^1,2 , Platonov Dmitry N. ² , Belyy Alexander Yu. ² , Novikov Maxim A. ^1,2 , Tomilov Yury V. ² , Anashkina Anastasia A. ¹ , Mukhina Kristina A. ¹ , Kechko Olga I. ¹ , Solyev Pavel N. ¹ , Novikov Roman A. ^1,2 , Makarov Alexander A. ¹ , Mitkevich Vladimir A. ¹

Affiliations

1	Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, 119991 Moscow, Russia
2	Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, 119991 Moscow, Russia

NADPH oxidase enzymes (NOXs) are a family of enzymes generating superoxide, which form reactive oxygen species. NOX2 activity is a causative agent for the progression of many diseases: neurodegenerative, cardiovascular, immune dysregulations, and even hereditary diseases and cancer. Administering antioxidants helps in inhibiting NOX2 activity; however, the development of selective inhibitors may provide greater improvement in the therapy of diseases. Here, an optimized synthesis of two most promising NOX2 inhibitors based on the 3-(indolin-6-yl)-4-(N-pyrazole-sulfonamide)-1H-pyrrolo [2,3-b]pyridine structure, namely, GSK2795039 and NCATS-SM7270, and an isomeric derivative of the same class, IMBIOC-1, is reported. The new modified procedures simplify the isolation, reduce byproduct formation, and improve the yields in 0.1–1 g scale preparations. Molecular modeling of the structures of NOX2 complexes with inhibitors validated their binding at the same site as NADPH, with IMBIOC-1 forming the largest number of intermolecular interactions with the NOX2 active site. Testing the effects of the compounds on amyloid beta-induced oxidative stress and toxicity in HMC3 microglial cells showed that all three inhibitors completely prevented the pathological amyloid-beta effect. At the same time, NCATS-SM7270 and IMBIOC-1 provided a stronger protective effect on microglial cell survival than GSK2795039, which allowed us to assert the potential of those compounds as neuroprotective agents.

Potapov K.V. , Platonov D.N. , Belyy A.Y. , Novikov M.A. , Tomilov Y.V. , Anashkina A.A. , Mukhina K.A. , Kechko O.I. , Solyev P.N. , Novikov R.A. , Makarov A.A. , Mitkevich V.A.
Improved Synthesis of Effective 3-(Indolin-6-yl)-4-(N-pyrazole-sulfonamide)-1H-pyrrolo[2,3-b]pyridine-Based Inhibitors of NADPH Oxidase 2
International Journal of Molecular Sciences. 2025. V.26. N8. 3647 . DOI: 10.3390/ijms26083647 Scopus OpenAlex

≡ Scopus:	2-s2.0-105003740237
≡ OpenAlex:	W4409435503