2-Thiazolylimino/Heteroarylimino-5-arylidene-4-thiazolidinones as New Agents with SHP-2 Inhibitory Action

Abstract

SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to continuously active enzyme were found in more than 50% of Noonan syndrome patients and are considered to be responsible for the high tendency of these patients to juvenile leukemias and other cancer types. Recently SHP-2 became a new drug target, but till now little has been done in this field. In the present study, 17 2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones divided into three series of derivatives bearing thiazole-, benzo[d]thiazole-, and benzo[d]isothizole rings were tested for SHP-2 inhibitory activity. Most of the compounds were good SHP-2 inhibitors. Benzo[d]thiazole derivatives exhibited the best inhibitory action. Docking studies revealed that hydrophobic interactions and hydrogen bond formation stabilize enzyme-inhibitor complex.

Thiazole-based chalcones as potent antimicrobial agents. Synthesis and biological evaluation

“…Our design supported from our previous findings [10][11][12][13][14][15] addressed the synthesis of a new class of structurally novel derivatives, that incorporate two known bioactive structures a thiazole [16][17][18][19][20][21][22][23][24][25][26] and a chalcone, [27][28][29] to yield a class of compounds with interesting antimicrobial properties…”

Antineoplastic activity of novel thiazole derivatives

“…Thiazole derivatives have attracted the interest of medicinal chemists due to a variety of their biological activities including antibacterial, anti-fungal, anti-HIV, anti-hypertension, anti-inflammatory, anti-cancer, anti-convulsive and anti-depressant [5][6][7][8][9][10]. The mechanisms of 1,3-thiazole derivatives antitumor activity may be associated with DNA intercalation [11,12], PRL-3, SHP-2 and JSP-1 inhibition [13][14][15][16], tumor necrosis factor (TNFα) [17], anti-apoptotic bio-complex Bcl-XL-BH3 [18], integrin avb3 [19], others. Thiazole ring belongs to the privileged scaffolds in modern medicinal chemistry [11,20,21], particularly at discovering new anticancer agents.…”

Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety

“…Mechanisms of 4-thiazolidinones and related heterocycles antitumor activity may be associated with the affinity to anticancer biotargets, such as phosphatase of a regenerating liver (PRL-3) [6,7], nonmembrane protein tyrosine phosphatase (SHP-2) [8], JNK-stimulating phosphatase-1 (JSP-1) [9], tumor necrosis factor TNFa [10], antiapoptotic biocomplex Bcl-X L -BH3 [11], integrin a v b 3 [12], etc.…”