Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis

Abstract

Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the c-KIT kinase protein. The stem cell factor receptor c-KIT was selected as target because most U.S. FDA-approved receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with 1,3,4-thiadiazole ( IIIa – m ) and aziridine ( VIa and VIc ) were afforded through a modified Schiff base green synthesis using β-cyclodextrin-SO 3 H in water as a recyclable proton-donor catalyst. A computational study found that indolin-2,3-dione forms a supramolecular inclusion complex with β-cyclodextrin-SO 3 H through noncovalent interactions. A molecular docking study of all the synthesized compounds was executed on the c-KIT kinase domain, and most compounds displayed binding affinities similar to that of Sunitinib. On the basis of the pharmacokinetic significance of the aryl thioether linkage in small molecules, 1,3,4-thiadiazole hybrids ( IIIa – m ) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones ( IVa – m ) via thioetherification using bis(triphenylphosphine)palladium(II)dichloride as the catalyst for C–S bond formation. Target compounds were tested against NCI-60 human cancer cell lines for a single-dose concentration. Among all three series of indolin-2-ones, the majority of compounds demonstrated broad-spectrum activity toward various cancer cell lines. Compounds IVc and VIc were further evaluated for a five-dose anticancer study. Compound IVc showed a potent activity of IC 50 = 1.47 μM against a panel of breast cancer cell lines, whereas compound VIc exhibited the highest inhibition for a panel of colon cancer cell lines at IC 50 = 1.40 μM. In silico ADME property descriptors of all the target molecules are in an acceptable range. Machine learning algorithms were used to examine the metabolites and phase I and II regioselectivities of compounds IVc and VIc , and the results suggested that these two compounds could be potential leads for the treatment of cancer.

Continuous flow reactions in the preparation of active pharmaceutical ingredients and fine chemicals

“…As is well known, aziridines 96 have significant value in the pharmaceutical, agrochemical, and material sciences areas. [105][106][107][108][109][110][111] In 2021, Noe ¨l with a slight collaboration of our group, proposed an electrochemical aziridination method involving internal alkenes 94 and primary amines 95 (Scheme 20). 112 In a homemade electrochemical flow reactor, the process delivered the products in up to 93% yield, with a residence time of only 5 minutes.…”

Recent advances in the accessibility, synthetic utility, and biological applications of aziridines

“…2). 106 Aziridines β-D-galactopyranoside derivatives were studied as anticancer agents by Calderón-Montaño and co-workers. The…”

The anti‐breast cancer potential of indole/isatin hybrids

“…[70,71] Mechanistically, hybrid 37 might suppress topoisomerase IIα to produce its antiproliferative properties. Isatin-1,3,4-thiadiazole hybrid 38 (GI 50 : 0.71-1.98 µM) revealed strong broad-spectrum efficacy against a panel of MCF-7, HS 578 T, BT549, T47D, MDA-MB-231, and MDA-MB-468 BC cell lines, [72] whereas hybrids 39a-c (IC 50 : 9.0 µM) were comparable to doxorubicin (IC 50 : 4.8 µM) against MCF-7 cancer cells. [73] Indole-tetrazole hybrids 40 (IC 50 : 4.15-77.26 µM) exhibited strong anti-MCF-7 cell activity, and the representative hybrids 40a,b (IC 50 : 4.15 and 5.42 µM) had greater potency than etoposide (IC 50 : 9.70 µM).…”

“…[ 70,71 ] Mechanistically, hybrid 37 might suppress topoisomerase IIα to produce its antiproliferative properties. Isatin‐1,3,4‐thiadiazole hybrid 38 (GI 50 : 0.71–1.98 µM) revealed strong broad‐spectrum efficacy against a panel of MCF‐7, HS 578 T, BT549, T47D, MDA‐MB‐231, and MDA‐MB‐468 BC cell lines, [ 72 ] whereas hybrids 39a–c (IC 50 : 9.0 µM) were comparable to doxorubicin (IC 50 : 4.8 µM) against MCF‐7 cancer cells. [ 73 ]…”