Synthesis and biological evaluation of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and -imidazoles: novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity

Abstract

A variety of benzylideneoxazoles, -thiazoles, and -imidazoles derived from 2,6-di-tert-butylphenol were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. The target compounds exhibit varying degrees of selectivity toward the two enzymes. Several compounds are orally active in the rat carageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models. Structure-activity relationships are discussed. From this work, (Z)-5-[[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-methylene]-2-imino-4-thiazolidinone methanesulfonate salt (CI-1004) was identified as a potent dual inhibitor of 5-lipoxygenase (IC50 = 0.77 microM) and cyclooxygenase (IC50 = 0.39 microM), with oral activity (ID40 = 0.6 mg/kg) in the rat MFE model of inflammation.

5-(4-Hydroxy-2,3,5-trimethylbenzylidene) thiazolidine-2,4-dione attenuates atherosclerosis possibly by reducing monocyte recruitment to the lesion

“…Many multisubstituted benzylidenethiazole analogs derived from 2,6-di-tert-butylphenol have been found to reduce inflammatory processes in vivo and in vitro by inhibiting both COX and 5-LOX (Unangst et al, 1994). Previously, we reported that one such analog, 5-(3,5-di-tert-butyl-4-hydroxybenzylidene) thiazolidin-2,4-dione (BHB-TZD), also possesses strong anti-atherogenic activity (Choi et al, 2010).…”

Property-based design and synthesis of new chloroquine hybrids via simple incorporation of 2-imino-thiazolidin-4-one or 1h-pyrrol-2, 5-dione fragments on the 4-amino-7-chloroquinoline side chain

“…Different reported methodologies on 2-imino-thiazolidin-4-one synthesis imply the isolation and purification of the corresponding thioureas as intermediates, and their subsequent chloroacetylation. [18][19][20] In this work, the quinoline derivatives bearing the 2-imino-tiazolidin-4-one framework 13 and 14 were obtained in good yields as white solids from the quinoline diamines 8, potassium thiocyanate, and chloroacetyl chloride in anhydrous acetone at room temperature, without isolation of thiourea derivatives 13a and 14a (Scheme 1, route A).…”

“…Physicochemical characteristics of the obtained compounds are given in Table 2. (13) General procedure for synthesis of chloroquine and 1H-pyrrol-2,5-dione hybrids (15)(16)(17)(18)(19)(20)(21)(22) 1.0 g (4.24 mmol) of quinoline diamines (8a or 8b) was dissolved in 5.0 mL of anhydrous dichloromethane under vigorous agitation. Then, a solution of anhydride (9-11) (0.7 g, 4.24 mmol) in dichloromethane was added dropwise to the above solution for 30 min at 0 °C, stirring the white precipitate formed for 2 h. Solvent excess was distilled under reduced pressure, and the remaining solid was filtered and washed with diethyl ether.…”

“…As well as thiazolidin-4-one systems, cyclic imides, e.g. 1H-pyrrol-2,5-diones 3, 4, are structural frameworks present in several active molecules, principally against cancer cell lines [16][17][18][19][20][21] (Figure 1). These properties are helpful activity modulators within of the development of new antimalarial agents.…”

Synthesis of 4-benzyl-1,3-thiazole derivatives as potential anti-inflammatory agents: An analogue-based drug design approach

“…It is di-tert-butyl phenol with thiazole molecular scaffold and has been identified as a dual inhibitor of cellular PGF 2 -alpha (COX pathway) and LTB 4 (LOX pathway) production [4,6]. Darbufelone is orally active and has been shown to be non-ulcerogenic in animal model of inflammation and arthritis [4,6].…”