Spirooxindoles as novel 3D-fragment scaffolds: Synthesis and screening against CYP121 from M. tuberculosis

Davis, Holly J.; Kavanagh, Madeline E.; Balan, Tudor; Abell, Chris; Coyne, Anthony G.

doi:10.1016/j.bmcl.2016.05.073

Cited by 19 publications

(17 citation statements)

References 53 publications

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“…tuberculosis [57], with known high-affinity binders that show potent activity in vitro and in cell-based assays [58,59]. A significant effort using fragment-based approaches targeting this enzyme led to the identification of several potent and selective inhibitors of CYP121 that have high ligand efficiency [60][61][62][63]. A fragment screening campaign was performed by Hudson and colleagues using DSF, NMR and ITC revealing several fragment hits [62].…”

Section: Thymidylate Kinasementioning

confidence: 99%

Targeting tuberculosis using structure-guided fragment-based drug design

Mendes

Blundell

2017

Drug Discovery Today

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Fragment-based drug discovery is now widely used in academia and industry to obtain small molecule inhibitors for a given target and is established for many fields of research including antimicrobials and oncology. Many molecules derived from fragment-based approaches are already in clinical trials and two - vemurafenib and venetoclax - are on the market, but the approach has been used sparsely in the tuberculosis field. Here, we describe the progress of our group and others, and examine the most recent successes and challenges in developing compounds with antimycobacterial activity.

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Section: Thymidylate Kinasementioning

confidence: 99%

Targeting tuberculosis using structure-guided fragment-based drug design

Mendes

Blundell

2017

Drug Discovery Today

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“…In recent years, spirocycles in general and spirooxindoles in particular have attracted much attention due to their unique structural aspects and their presence in a number of bioactive natural products [34,35]. Naturally occurring and synthetic spirooxindoles display a wide array of pharmacological activities including anti-cancer [36,37], anti-inflammatory [38], antimicrobial [35], antimalarial [39], antitubercular [40], antileishmanial [41], anti-cholinesterase [35] and anti-viral [42], activity, and therefore continue to attract interest as leads in drug discovery. Among naturally occurring spirooxindoles, the spiro[ pyrrolidine-2 : 3-oxindole] scaffold (found in elacomine, horsfiline and rhynchophylline) appears quite frequently.…”

Section: Introductionmentioning

confidence: 99%

3′,4′-Dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as potential anti-cancer agents: synthesis and preliminary screening

Lobe

Efange

2020

R. Soc. open sci.

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Both tetrahydroisoquinolines (THIQs) and oxindoles (OXs) display a broad range of biological activities including anti-cancer activity, and are therefore recognized as two privileged scaffolds in drug discovery. In the present study, 24 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, designed as molecular hybrids of THIQ and OX, were synthesized and screened in vitro against 59 cell lines in the NCI-60 screen. Twenty compounds displayed weak to moderate inhibition of cell proliferation; among them, three compounds displayed at least 50% inhibition of cell proliferation. The compounds appeared to target primarily renal cell cancer lines; however, leukaemia, melanoma, non-small cell lung cancer, prostate, ovarian and even breast cancer cell lines were also affected. Therefore, this class of spirooxindoles may provide useful leads in the search for new anti-cancer agents.

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“…For example, oxindole derivatives recently emerged as privileged scaffolds in the modulation of adenosine monophosphate-activated protein kinase (AMPK) [ 7 ], and 2-oxindole-based hydrazides are potent cytotoxic agents with apoptotic induction properties [ 8 ]. Substituted oxindoles are also very interesting building blocks for their role as starting materials toward more complex oxindole-based structures such as spirooxindoles [ 9 , 10 ]. Original piperidinoyl spirooxindoles can be obtained in very high yields and with excellent enantioselectivities via the hetero-Diels–Alder reaction between 2-aza-3-silyloxy-butadienes and alkylidene oxindoles [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2-Mercapto-(2-Oxoindolin-3-Ylidene)Acetonitriles from 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-ones

et al. 2018

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Alkylidene oxindoles are important functional moieties and building blocks in pharmaceutical and synthetic chemistry. Our interest in biologically active compounds focused our studies on the synthesis of novel oxindoles, bearing on the exocyclic double bond at the C8, CN, and S groups. Extending the potential applications of Appel’s salt, we developed a new synthetic approach by investigating the reactions of C5-substituted 2-oxindoles with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) to give original (Z)-3-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)indolin-2-one derivatives, and new 2-mercapto-(2-oxoindolin-3-ylidene)acetonitriles via a dithiazole ring-opening reaction. The work described in this article represents further applications of Appel’s salt in the conception of novel heterocyclic rings, in an effort to access original bioactive compounds. Fifteen new compounds were prepared and fully characterized.

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Spirooxindoles as novel 3D-fragment scaffolds: Synthesis and screening against CYP121 from M. tuberculosis

Cited by 19 publications

References 53 publications

Targeting tuberculosis using structure-guided fragment-based drug design

Targeting tuberculosis using structure-guided fragment-based drug design

3′,4′-Dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as potential anti-cancer agents: synthesis and preliminary screening

Synthesis of 2-Mercapto-(2-Oxoindolin-3-Ylidene)Acetonitriles from 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-ones

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