Synthesis, crystal structure and in silico studies of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones

Patel, Subham G.; Vala, Ruturajsinh M.; Patel, Paras J.; Upadhyay, Dipti B.; Ramkumar, V.; Gardas, Ramesh L.; Patel, Hasmukh S.

doi:10.1039/d2ra02694e

Cited by 32 publications

(25 citation statements)

References 44 publications

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“…Among these, quinolones attracted our attention, because of their low cytotoxicity on Vero cells (CC50 > 200 µ M) compared to the other compounds isolated [4] and because of their easy access by synthesis [5,6], facilitating the preparation of various analogs. Furthermore, quinoline derivatives are compounds of choice because they are known to possess a wide range of biological properties including anti-leishmanial activities [7][8][9][10][11][12]. They are considered as privileged structures in drug development [13,14].…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

et al. 2022

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Quinoline derivatives and especially quinolones are considered as privileged structures in medicinal chemistry and are often associated with various biological properties. We recently isolated a series of original monoterpenyl quinolones from the bark of Codiaeum peltatum. As this extract was found to have a significant inhibitory activity against a Leishmania species, we decided to study the anti-leishmanial potential of this type of compound. Leishmaniasis is a serious health problem affecting more than 12 million people in the world. Available drugs cause harmful side effects and resistance for some of them. With the aim of finding anti-leishmanial compounds, we developed a synthetic strategy to access natural quinolones and analogues derived from zanthosimuline. We showed the versatility of this natural compound toward cyclization conditions, leading to various polycyclic quinolone-derived structures. The natural and synthetic compounds were evaluated against amastigote forms of Leishmania infantum. The results obtained confirmed the interest of this family of natural compounds but also revealed promising activities for some intermediates deriving from zanthosimuline. Following the same synthetic strategy, we then prepared 14 new analogues. In this work, we identified two promising molecules with good activities against intramacrophage L. infantum amastigotes without any cytotoxicity. We also showed that slight changes in amide functional groups affect drastically their anti-parasitic activity.

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Section: Resultsmentioning

confidence: 99%

“…13 C NMR (125 MHz, CDCl 3 , 25 [M+H] + 310.1802, found 310.1799. 1,1,3a,9-Tetramethyl-1,1a,1a1,2,3,3a,9,10b-octahydro-10H-4-oxa-9-azacyclobuta [7,1]indeno [5,6-a]naphthalen-10-one (12). To a solution of zanthosimuline 7 (50 mg, 0.16 mmol, 1 eq.)…”

Section: Procedures and Analytical Description Of Compoundsmentioning

confidence: 99%

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

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“…In our previous work, 2,4-dimethoxy-THPQs were synthesised by conventional heating in acetic acid medium. 21 To improve the protocol, irradiation of microwave was used for acceleration of multicomponent synthesis. Irradiation of microwave was used in the synthesis of heterocycle because it offers unique advantages.…”

Section: Introductionmentioning

confidence: 99%

Microwave-assisted multicomponent synthesis of antiproliferative 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones

et al. 2022

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“…Both methods produce pyrano[2,3-c]pyrazoles, but substitutions at C-4 are different. In continuation of works on aldehyde based three-component reactions [ 33–39 ], in current work, we synthesised N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles by aldehyde based DABCO catalysed three-component reaction ( Scheme 3 ). We further report 4j as the first pyrano[2,3-c]pyrazole derivative with kinase inhibitory and anti-glioma potency from within the series.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles enabling PKBβ/AKT2 inhibitory and in vitro anti-glioma activity

et al. 2022

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A series of N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity against primary patient-derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds was evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed, AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells and exhibited potent EC 50 against glioblastoma cell lines. Although exhibiting potency against glioma cells, 4j exhibited significantly less cytotoxicity against non-cancerous cells even at fourfold–fivefold the concentration. Herein we establish a novel biochemical kinase inhibitory function for N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles and further report their anti-glioma activity in vitro for the first time. KEY MESSAGE Anti-glioma pyrano[2,3-c]pyrazole 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. 4j also displayed PKBβ/AKT2 inhibitory activity. 4j is nontoxic towards non-cancerous cells.

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Synthesis, crystal structure and in silico studies of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones

Abstract: Single-crystal XRD analysis of 2,4-dimethoxy THPQs and their relative reactivity with properties were investigated using DFT calculation. Molecular docking studies show they effectively docked with main protease of SARS-CoV-2.

Cited by 32 publications

References 44 publications

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

Microwave-assisted multicomponent synthesis of antiproliferative 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones

Synthesis of N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles enabling PKBβ/AKT2 inhibitory and in vitro anti-glioma activity

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