One-Pot Diastereoselective Synthesis of Spiro[pyrimidine-5,8′-thiazolo[5,4-f]quinoline]triones and Diimidazo-pyrazinyl-bis(1,3-dimethyl-2,4,6-trioxohexahydropyrimidine-5-ylium)dihydrate as Anticancer Agents

TY - JOUR

T1 - One-Pot Diastereoselective Synthesis of Spiro[pyrimidine-5,8′-thiazolo[5,4-f]quinoline]triones and Diimidazo-pyrazinyl-bis(1,3-dimethyl-2,4,6-trioxohexahydropyrimidine-5-ylium)dihydrate as Anticancer Agents

AU - Parmar, Mehul P.

AU - Chaudhari, Hrushikesh S.

AU - Vala, Disha P.

AU - Macwan, Pradip M.

AU - Nogales, Joaquina

AU - Sahoo, Subash C.

AU - Salunke, Deepak B.

AU - Banerjee, Sourav

AU - Chandra Sekhar, Kondapalli Venkata Gowri

AU - Khan, Adam N.

AU - Padrón, José M.

AU - Patel, Hitendra M.

N1 - Publisher Copyright: © 2026 American Chemical Society

PY - 2026/6/26

Y1 - 2026/6/26

N2 - The development of nitrogen- and sulfur-containing heterocycles remains a central challenge in modern synthetic chemistry owing to their structural diversity and biological relevance. Herein, we report the synthesis of the ionic liquid (IL) 1-dodecyl-1-methylpiperidinium chloride ([C12mpip][Cl]) and, for the first time, its application as an efficient catalyst in an unprecedented divergent one-pot cyclization. The protocol enables the cyclization of 6-aminobenzothiazole with diverse aryl or heteroaryl aldehydes and 1,3-dimethylbarbituric acid in ethanol as a green solvent under reflux conditions. Apart from ortho-substituted and NH-unsubstituted heteroaryl aldehydes, the reaction proceeds with high regio- and diastereoselectivity to afford spiro[pyrimidine-5,8′-thiazolo[5,4-f]quinoline]triones 4(a–l) in yields of up to 94% and diastereomeric ratios exceeding >99:1 (syn:anti). Notably, the reaction outcome is governed by the aldehyde substitution pattern, enabling controlled access to structurally distinct fused heterocycles under identical conditions. The method constructs two new stereogenic centers and multiple σ-bonds in a single operation and is readily scalable to the gram scale with consistently high yields. All structures were confirmed by spectroscopic techniques and single-crystal X-ray analysis. Antiproliferative evaluation across six solid tumor cell lines identified compound 4l as a lead candidate, displaying uniform single-digit micromolar GI50 values (1.22–7.40 μM) and potent activity against patient-derived glioblastoma (GBM6) cells (GI50 = 2.40 μM). Compound 5b also exhibited consistent low-micromolar growth inhibition across multiple cancer cell lines. The operational simplicity, scalability, and promising biological profile facilitated gram-scale synthesis with yields of up to 94%.

AB - The development of nitrogen- and sulfur-containing heterocycles remains a central challenge in modern synthetic chemistry owing to their structural diversity and biological relevance. Herein, we report the synthesis of the ionic liquid (IL) 1-dodecyl-1-methylpiperidinium chloride ([C12mpip][Cl]) and, for the first time, its application as an efficient catalyst in an unprecedented divergent one-pot cyclization. The protocol enables the cyclization of 6-aminobenzothiazole with diverse aryl or heteroaryl aldehydes and 1,3-dimethylbarbituric acid in ethanol as a green solvent under reflux conditions. Apart from ortho-substituted and NH-unsubstituted heteroaryl aldehydes, the reaction proceeds with high regio- and diastereoselectivity to afford spiro[pyrimidine-5,8′-thiazolo[5,4-f]quinoline]triones 4(a–l) in yields of up to 94% and diastereomeric ratios exceeding >99:1 (syn:anti). Notably, the reaction outcome is governed by the aldehyde substitution pattern, enabling controlled access to structurally distinct fused heterocycles under identical conditions. The method constructs two new stereogenic centers and multiple σ-bonds in a single operation and is readily scalable to the gram scale with consistently high yields. All structures were confirmed by spectroscopic techniques and single-crystal X-ray analysis. Antiproliferative evaluation across six solid tumor cell lines identified compound 4l as a lead candidate, displaying uniform single-digit micromolar GI50 values (1.22–7.40 μM) and potent activity against patient-derived glioblastoma (GBM6) cells (GI50 = 2.40 μM). Compound 5b also exhibited consistent low-micromolar growth inhibition across multiple cancer cell lines. The operational simplicity, scalability, and promising biological profile facilitated gram-scale synthesis with yields of up to 94%.

UR - https://www.scopus.com/pages/publications/105042855098

U2 - 10.1021/acs.joc.6c00482

DO - 10.1021/acs.joc.6c00482

M3 - Article

C2 - 42283810

AN - SCOPUS:105042855098

SN - 0022-3263

VL - 91

SP - 8536

EP - 8554

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

IS - 25

ER -