5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases

Maccari, Rosanna; Paoli, Paolo; Ottanà, Rosaria; Jacomelli, Michela; Ciurleo, Rosella; Manao, Giampaolo; Steindl, Theodora M.; Langer, Thierry; Vigorita, Maria Gabriella; Camici, Giovanni G.

doi:10.1016/j.bmc.2007.05.027

Cited by 102 publications

(60 citation statements)

References 66 publications

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“…The phenoxy and benzyloxy groups on the 5-arylidene moiety bring about enhanced PTP1B inhibitory activity compared to non-aromatic substituents, improving the stability of the enzyme/inhibitor complex, especially when inserted in the para position [53,55]. The inhibitory ability of compounds 7 and 8 against selected PTPs proved to be in close agreement with the structureeactivity relationships already acquired for this class of inhibitors.…”

Section: Resultssupporting

confidence: 75%

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New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

Ottanà

Maccari

Amuso

et al. 2012

European Journal of Medicinal Chemistry

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a b s t r a c tIn pursuing our research targeting the identification of potent inhibitors of PTP1B and LMW-PTP, we have identified new 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids endowed with interesting in vitro inhibitory profiles. Most compounds proved to be inhibitors of PTP1B and LMW-PTP isoform IF1. The tested inhibitors also showed selectivity towards PTP1B over the closely related TC-PTP. These compounds were found to activate the insulin-mediated signalling on mouse C2C12 skeletal muscle cells by increasing the phosphorylation levels of the insulin receptor and promoting cellular 2-deoxyglucose uptake.Interestingly, 4-{[5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylimino)-4-oxo-3-thiazolidinyl] methyl}benzoic acid (7d), the best in vitro inhibitor of PTP1B and the isoform IF1 of LMW-PTP, provided the highest activation level of the insulin receptor and was found to be endowed with an excellent insulinomimetic effect on the selected cells. This compound therefore represents an interesting lead compound for developing novel PTP1B and LMW-PTP inhibitors which could be achieved by improving both its pharmacological profile and its potentiating effects on insulin signalling.

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Section: Resultssupporting

confidence: 75%

“…Interesting results have been achieved obtaining potent PTP inhibitors endowed with IC 50 values at submicromolar levels. They have been shown to act as competitive and reversible PTP inhibitors with significant selectivity for PTP1B and the IF1 isoform of LMW-PTP [53,54].…”

Section: Introductionmentioning

confidence: 99%

New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

Ottanà

Maccari

Amuso

et al. 2012

European Journal of Medicinal Chemistry

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“…[25] In fact, inserting monoanionic pTyr mimics into optimal templates is considered to be a valid method to obtain inhibitors with low polarity.…”

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confidence: 99%

Structure‐Based Optimization of Benzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B and Low Molecular Weight Protein Tyrosine Phosphatase

Maccari¹,

Ottanà²,

Paoli

et al. 2009

ChemMedChem

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We have optimized previously discovered benzoic acids 1, which are active as inhibitors of PTP1B and LMW-PTP, two protein tyrosine phosphatases that have emerged as attractive targets for the development of novel therapeutic agents for the treatment of diabetes, obesity, and cancer. Our efforts led to the identification of new and more potent analogues with appreciable selectivity toward human PTP1B and the IF1 isoform of human LMW-PTP.

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“…Thiazolidinone moiety is an important structure element in medicinal chemistry [2][3][4][5][6] and substituted thiazolidinones show a broad spectrum of biological activities [7][8][9][10][11] [16].Therefore, facile preparation of various 5-arylidene thiazolidinones is highly desirable. In continuation of our ongoing interests in the development of benign methods targeted at the synthesis of biologically important heterocycles [17][18][19], we used base supported ionic liquid-like phase (SILLP) [20] as an efficientand recyclablesolid phasecatalystinthe synthesis of thetitle compound.…”

Section: Discussionmentioning

confidence: 99%

“…Thiazolidinone moiety is an important structure element in medicinal chemistry [2][3][4][5][6] and substituted thiazolidinones show a broad spectrum of biological activities [7][8][9][10][11]. In particular, 5-arylidene-4-thiazolidinones have been synthesized and employed as new agents with SHP-2 inhibitory action [12],aspotential antifungal and antibacterial drugs [13],asPTP1Band LMW-PTP inhibitors [14],a nti-inflammatory agent [15] and antimicrobial drugs [16].Therefore, facile preparation of various 5-arylidene thiazolidinones is highly desirable.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (2Z,5Z)-3-allyl-5-(4-(methylthio)benzylidene)- 2-(p-tolylimino)thiazolidin-4-one, C21H20N2OS2

Mamaghani¹,

Joshari²,

Tabatabaeian³

et al. 2011

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialTo as olution of 3-allyl-2-(p-tolylimino)thiazolidin-4-one (3 mmol) and base supported ionic liquid-like phase (SILLP) (0.5 g) in ethanol (20 mL), 4-methylthiobenzaldehyde (3 mmol) was added and the mixture was heated at reflux for 3h.S ILLP was separated by filtration. Then the solution was concentrated in vacuum and kept at -15 ºC over 2h.The residue was filtered off and recrystallized from methanol to give 3-allyl-5-(4-(methylthio)benzylidene)-2-(p-tolylimino)thiazolidin-4-one as ayellow solid in 87 %yield (m.p. =138-140°C). Elemental analysisfound: C, 66.13 %; H, 5.35 %; N, 7.47 %; calculated for C 21 H 20 N 2 OS 2 :C,66.28 %; H, 5.30 %; N, 7.36 %. Melting points were measured on aElectrothermal 9100 instrument and are uncorrected. Elemental analyses were made by aC arlo-Erba EA1110CNNO-S analyzer. Experimental detailsAll hydrogen atomswere refined in isotropic approximation in a riding model with U iso (H) =1 .2 U eq (C). The structure was checked with PLATON [1] and no solvent accesible void was found. The residual densities are 0.32 eÅ -3 (highest peak at 1.24 Åfrom C13) and -0.21 eÅ -3 (deepest hole at 0.61 Åfrom H12). DiscussionThiazolidinone moiety is an important structure element in medicinal chemistry [2][3][4][5][6] and substituted thiazolidinones show a broad spectrum of biological activities [7][8][9][10][11] [16].Therefore, facile preparation of various 5-arylidene thiazolidinones is highly desirable. In continuation of our ongoing interests in the development of benign methods targeted at the synthesis of biologically important heterocycles [17][18][19], we used base supported ionic liquid-like phase (SILLP) [20] as an efficientand recyclablesolid phasecatalystinthe synthesis of thetitle compound. The X-ray diffractometric analysis of the title product was carried out on the single crystal prepared in peteroleum ether/EtOAc(4:1). The packing in the title crystal structure can be described as asuccessionofparallel layers.The conjugationbetween C=Oand the amiden itrogeni se vident from thev alue of theb ondl ength d(Nl-C10) =1.362(5)Å.The thiazole ring is planar as indicated by torsion angles ÐC9-C10-N1-C14 =-3.4(5)°, ÐN1-C10-C9-S2 =0.4(4)°, ÐC10-C9-S2-C14 =1.8(3)°and ÐN1-C14-S2-C9 =-36(3)°. In addition, the torsion angles ÐS2-C14-N2-C15 =0 .8(6)°, ÐO1-C10-N1-C11 =1 .2(6)°, ÐN2-C14-N1-C11 =1.8(6)°, ÐC5-C8-C9-S2 =-1.0(7)°and ÐN1-C10-C9-S2 =0 .4(4)°revealed that the thiazole ring is coplanar with O1, N2,C 5, C8,C 11 and C15.T he distances.362(5) Åagree with the literature reports [21][22][23][24][25]. The bond length d(C14-N2) =1.259(5) Åand the angles ÐN2-C14-S2 =128.2(3)°and ÐN2-C14-N1 =121.8(4)°con-firm the imine nature of the N2-C14 bond. The distance d(C8-C9)=1.331(5) Åand the angles ÐC8-C9-S2 =129.7(3)°a nd ÐC8-C9-C10 =120.5(3)°are consistant with double bond features of C8-C9.This analysis also unambiguously confirmed the Z configuration at the chiral axis and this is quite evident from the spatial orientation of arylg roups attached to C14-N2 and C8-C9 double bonds.

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5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases

Cited by 102 publications

References 66 publications

New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

Structure‐Based Optimization of Benzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B and Low Molecular Weight Protein Tyrosine Phosphatase

Crystal structure of (2Z,5Z)-3-allyl-5-(4-(methylthio)benzylidene)- 2-(p-tolylimino)thiazolidin-4-one, C21H20N2OS2

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