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. 2016 Jun 18;21(6):794.
doi: 10.3390/molecules21060794.

Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation

Damien Hédou  1 , Carole Dubouilh-Benard  2 , Nadège Loaëc  3   4 , Laurent Meijer  5 , Corinne Fruit  6 , Thierry Besson  7
Affiliations

Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation

Damien Hédou et al. Molecules. .

Abstract

A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer's disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases.

Keywords: CDK5; CK1; CLK1; DYRK1A; GSK-3; Hügershoff reaction; microwave-assisted synthesis; protein kinases; thiazolo[5,4-f]quinazolin-9(8H)-ones.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
General formula of lead kinases inhibitors previously described [25] and new targeted molecules.
Figure 2
Figure 2
(a) Schematic representation of binding mode of one of the lead compounds in the ATP-binding site of GSK-3; (b) Description of the aminoalkyl and aryl substituents envisioned in position 2 of the thiazole with the aim of a better affinity and selectivity for target kinases (e.g., GSK-3).
Scheme 1
Scheme 1
Envisioned retrosynthetic pathway for the synthesis of the target products, via Hügershoff reaction [29,30,31] or transition metal-catalyzed intramolecular C-S bond formation [32,33,34,35,36].
Scheme 2
Scheme 2
Sequential MCR procedure for convenient synthesis of 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) from 1. Reagents and conditions: (a) Step 1: DMFDMA (2.5 equiv), DMF, 100 °C (µw), 15 min; Step 2: Cyclopropylamine (1.1 eq), AcOH, 100 °C (µw), 15 min; 85%; (b) HCO2NH4 (5.0 equiv), Pd/C (10%), EtOH, 85 °C (μw), 15 min; 85%.
Scheme 3
Scheme 3
Synthetic routes for access to the key isothiocyanate 4.
Scheme 4
Scheme 4
Synthesis of isothiocyanates 7a–l from amines 3 or from isothiocyanates 4.
Scheme 5
Scheme 5
Hügershoff cyclization mechanism applied to thiourea 7a and compounds 8a, 9a and 10a identified.
Scheme 6
Scheme 6
Synthesis of 8-cyclopropyl-2-(arylamino)thiazolo[5,4-f]quinazolin-9(8H)-ones 8b–f and their pyrido analog 8g.
Scheme 7
Scheme 7
Hügershoff conditions applied to 7l giving the corresponding 2-substituted benzothiazole 10l selectively.
Scheme 8
Scheme 8
Synthesis of thiourea 12 via condensation of aniline with isothiocyanate 13.
Scheme 9
Scheme 9
General description of the intramolecular metal-catalyzed cyclization of 12.
Scheme 10
Scheme 10
One-pot sequential CuI catalyzed intramolecular cyclization of intermediates thioureas (from 13) for the synthesis of series 8 and 14.
Scheme 11
Scheme 11
Synthesis of carboximidamides 17a–f from brominated amine 11.
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References

    1. Wells G., Bradshaw T.D., Diana P., Seaton A., Shi D.-F., Westwell A.D., Stevens M.F.G. Antitumor benzothiazoles. Part 10. The synthesis and antitumor activity of benzothiazole substituted quinol derivatives. Bioorg. Med. Chem. Lett. 2000;10:513–515. - PubMed
    1. Bradshaw T.D., Wrigley S., Shi D.-F., Schultz R.J., Paull K.D., Stevens M.F.G. 2-(4-Aminophenyl)benzothiazoles: Novel agents with selective profiles of in vitro anti-tumour activity. Br. J. Cancer. 1998;77:745–752. doi: 10.1038/bjc.1998.122. - DOI - PMC - PubMed
    1. Molinski T.F. Marine pyridoacridine alkaloids: structure, synthesis, and biological chemistry. Chem. Rev. 1993;93:1825–1838. doi: 10.1021/cr00021a009. - DOI
    1. Gunawardana G.P., Kohmoto S., Gunasekara S.P., McConnel O.J., Koehn F.E. Dercitine, a new biologically active acridine alkaloid from a deep water marine sponge, Dercitus sp. J. Am. Chem. Soc. 1988;110:4856–4858. doi: 10.1021/ja00222a071. - DOI
    1. Gunawardana G.P., Kohmoto S., Burres N.S. New cytotoxic acridine alkaloids from two deep water marine sponges of the family Pachastrellidae. Tetrahedron Lett. 1989;30:4359–4362. doi: 10.1016/S0040-4039(00)99360-2. - DOI

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