Synthesis, Characterization, and In Silico Studies of Novel Spirooxindole Derivatives as Ecto-5′-Nucleotidase Inhibitors

Abstract

Ecto-5′-nucleotidase (ecto-5′-NT, CD73) inhibitors are promising drug candidates for cancer therapy. Traditional efforts used to inhibit the ecto-5′-nucleotidase have involved antibody therapy or development of small molecule inhibitors that can mimic the acidic and ionizable structure of adenosine 5′monophosphate (AMP). Herein, we report an efficient, environment friendly route for the synthesis of non-nucleotide based small molecules, i.e., substituted spirooxindole derivatives 9a−9l and investigated their inhibitory potential on human and rat recombinant ecto-5′-nucleotidase isozymes. These attempts have resulted in the identification of compound 9f (IC 50 = 0.15 ± 0.02 μM) inhibitor on h-ecto-5′-NT which showed 280-fold higher inhibition and compound 9h (IC 50 ± 0.19 ± 0.03 μM) on r-ecto-5′-NT with 406-fold enhanced inhibition than reference standard sulfamic acid. Moreover, in silico studies were carried out to assess binding interactions of potent compounds within enzyme active sites and demonstrated excellent correlation with the experimental findings.

Highly efficient, catalyst-free, one-pot sequential four-component synthesis of novel spiroindolinone-pyrazole scaffolds as anti-Alzheimer agents: in silico study and biological screening

“…27–29 Isatin and its derivatives are fascinating and versatile building blocks widely used to synthesize important and bioactive heterocyclic compounds. 30–35…”

“…[27][28][29] Isatin and its derivatives are fascinating and versatile building blocks widely used to synthesize important and bioactive heterocyclic compounds. [30][31][32][33][34][35] The spirooxindole framework 36,37 is a significant structural arrangement found in various bioactive natural compounds, including horsfiline, coerulescine, spirotryprostatin A, welwitindolinone A, elacomine, and alstonisine. Spirotryprostatin A, a natural alkaloid obtained from the fermentation broth of Aspergillus fumigatus, has been recognized as a new inhibitor of microtubule assembly.…”

Editorial: Metalloenzymes: Potential Drug Targets

“…Moreover, the development of ecto-5′-nucleotidase inhibitors may also serve to treat cancer (Iqbal et al, 2013). The heterocyclic compounds which have been synthesized and screened as NTPDases include oxoindolin phenylhydrazine carboxamides (Afzal et al, 2021), pyrrolo[2,3-b]pyridine derivatives (Ullah et al, 2021), spirooxindole derivatives (Ashraf et al, 2020), sulfonylhydrazones (Younus et al, 2020), 2-substituted-7trifluoromethyl-thiadiazolopyrimidones (Afzal et al, 2020), pyrazolyl pyrimidinetrione, and thioxopyrimidinedione conjugates as selective inhibitors of human ectonucleotidase (Andleeb et al, 2019), etc. Furthermore, the review articles of Iqbal (Iqbal, 2019) have also reported the importance of ectonucleotidase inhibitors in the treatment of various diseases.…”