Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases

Abstract

Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regulating the levels of nucleotides in extracellular environment. However, the pathophysiological functions of these enzymes are not fully understood due to lack of potent and selective NTPDase inhibitors. Herein, a series of oxoindolin hydrazine carbothioamide derivatives is synthesized and screened for NTPDase inhibitory activity. Four compounds were identified as selective inhibitors of h-NTPDase1 having IC50 values in lower micromolar range, these include compounds 8b (IC50 = 0.29 ± 0.02 µM), 8e (IC50 = 0.15 ± 0.009 µM), 8f (IC50 = 0.24 ± 0.01 µM) and 8l (IC50 = 0.30 ± 0.03 µM). Similarly, compound 8k (IC50 = 0.16 ± 0.01 µM) was found to be a selective h-NTPDase2 inhibitor. In case of h-NTPDase3, most potent inhibitors were compounds 8c (IC50 = 0.19 ± 0.02 µM) and 8m (IC50 = 0.38 ± 0.03 µM). Since NTPDase3 has been reported to be associated with the regulation of insulin secretion, we evaluated our synthesized NTPDase3 inhibitors for their ability to stimulate insulin secretion in isolated mice islets. Promising results were obtained showing that compound 8m potently stimulated insulin secretion without affecting the NTPDase3 gene expression. Molecular docking studies of the most potent compounds were also carried out to rationalize binding site interactions. Hence, these compounds are useful tools to study the role of NTPDase3 in insulin secretion.

2‐Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors

“…In the 3-position, a cyano group (10,19,20), an ethylcarboxylic acid ester (1-4, 11-15, 17), or a tert-butylcarboxylic acid ester (5-9, 16, 18, 21-32) was present. Position 2 was substituted with an amino group (1-10), a benzamido residue (11), a thiourea group (12)(13)(14)(15)(16)(17)(18)(19), a cyclized isothiourea group (20), a urea (21)(22)(23)(24)(25)(26)(28)(29)(30)(31)(32), or a carbamate (27) function. R 1 position: A small aliphatic methyl or ethyl substituent resulted in inactive compounds (1, 2, 5, and 6), while a larger, more lipophilic isobutyl residue restored some potency (compound 7); however, a benzyl residue was superior (4,8,10).…”

“…Only a few small molecule inhibitors of CD39 have been described so far, all of which show limited potency and/or lack of metabolic stability. [26][27][28][29][30][31][32] Nucleotide derivatives, analogs of the natural substrates, have been investigated, for example, ARL 67156 (I) and its derivatives (e.g., II). [27,33,34] Nonnucleotide inhibitors comprise polyoxometalates (POMs, e.g., III), anthraquinones, and various other heterocyclic compounds including the clinically approved drugs ticlopidine (IV) and clopidogrel (V), and indole derivatives such as VI.…”

“…[27,33,34] Nonnucleotide inhibitors comprise polyoxometalates (POMs, e.g., III), anthraquinones, and various other heterocyclic compounds including the clinically approved drugs ticlopidine (IV) and clopidogrel (V), and indole derivatives such as VI. [28][29][30][31]35,36] In contrast, CD73 inhibitors with nano-or even picomolar potency have been developed, for example, PSB-12489 (VII), and AB680 (VIII), which is currently being studied in clinical trials for the treatment of cancer. [37][38][39][40][41] Furthermore, potent nonnucleotidic CD73 inhibitors have been published, for example, IX (see Figure 1).…”

Synthesis, crystal structure, and antidiabetic property of hydrazine functionalized Schiff base: 1,2-Di(benzylidene)hydrazine

“…The expanding research on the hydrazine-based molecule is evident from the world hydrazine market value which is US$424 million in 2020 as per the report by Future Market Insight (FMI) and in 2021 the value surpassed US$426 million [8]. On the verge of the development of efficient hydrazine-based materials, many functionalizations have been achieved [9][10][11][12]. The functionalization of hydrazine improves the efficiency of the materials and may create new properties in it.…”

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.…”