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[Display omitted] • Thymol – 4-thiazolidinone hybrids as multitarget colorectal cancer inhibitors (CRC). • Inhibition of COX-2, 5-LOX and PIM-1 kinase is effective in the treatment of CRC. • 5a, 5c, 5f and 5g showed in vitro and in vivo anti-inflammatory activities. • 5d, 5e and 5g induced caspase 3\7 dependent-apoptosis in vitro in human CRC. • 5g achieved the target goal and acted as multitarget inhibitor of human CRC. Colorectal cancer (CRC) is the second cause of cancer death worldwide. Inhibitors of COX-2, 5-LOX and PIM-1 kinase were very effective in the treatment and prevention of CRC in mouse models in vivo. Furthermore, thymol was confirmed to inhibit CRC cell proliferation in cancer cell lines and inhibitory activity against COX-2 and 5-LOX. On the other hand, 4-thiazolidinone pharmacophore was incorporated in the structures of various reported COX-2, 5-LOX and PIM kinase inhibitors. Consequently, the aim of the present investigation was to combat CRC by synthesis and biological evaluation of new thymol – 4-thiazolidinone hybrids as multitarget anticancer agents that could inhibit the key COX-2, 5-LOX and PIM-1 kinase enzymes simultaneously. Compounds 5a - d and 5g displayed inhibitory activity against COX-2 nearly equal to Celecoxib with high selectivity index (SI). Moreover, compounds 5b-e showed 5-LOX inhibitory activity nearly equal to the reference Quercetin while compounds 5a , 5f and 5g elicited inhibitory activity slightly lower than Quercetin. Furthermore, in vivo formalin-induced paw edema test revealed that, compounds 5a, 5c, 5f and 5g showed higher % inhibition than Celecoxib and compounds 5a, 5f and 5g showed higher % inhibition than Diclofenac sodium. In addition, compounds 5a-c, 5e-g showed in vivo superior gastrointestinal safety profile as Celecoxib in fasted rats. Besides, compounds 5d, 5e and 5g exhibited the highest activity against human CRC cell lines (Caco-2 and HCT-116) at doses less than their EC 100 on normal human cells. Furthermore, compounds 5e and 5g induced apoptosis-dependent death by above 50% in the treated CRC cell lines. Moreover, compounds 5e and 5g induced caspase activation by >50% in human CRC. Also, compounds 5d, 5e and 5g showed in vitro inhibitory activity against both PIM-1\2 kinases comparable to the reference Staurosporine. In silico docking studies were concordant with the biological results. In conclusion, compound 5g, of simple chemical structure, achieved the target goal of inhibiting three targets leading to inhibition of human CRC cell proliferation. It inhibited the target key enzymes COX-2, 5-LOX and PIM-1\2 kinase in vitro. Besides, it revealed in vitro inhibition of cell proliferation in cancer cell lines via activation of caspase 3\7 dependent-apoptosis in human CRC cell lines. In addition, it elicited in vivo anti-inflammatory activity in formalin-induced paw edema test and in vivo oral safety in gastric ulcerogenic activity test. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel pyrimidine-5-carbonitrile hybrid with 1,3-thiazole moiety 8a-p as anti-inflammatory EGFR inhibitors has been designed and synthesized. • 8h , 8n and 8p showed potent COX-2 inhibition. • 8h , 8n and 8p decrease the pro-inflammatory cytokines (PGE2, TNF-a, IL-6), iNO and MDA with no effect on heart rate or blood pressure. • Docking study revealed high binding affinities toward COX-2 and EGFR with the formation of essential hydrogen bonds. A new series of pyrimidine-5-carbonitrile derivatives 8a-p carrying the 1,3-thiazole moiety has been designed and synthesized as novel anti-inflammatory EGFR inhibitors with cardiac and gastric safety profiles. 8a-p have been assessed for their inhibitory activity against COX-1/COX-2 activity. Compounds 8h , 8n , and 8p were found to be potent and selective COX-2 inhibitors (IC 50 = 1.03–1.71 μM) relative to celecoxib (IC 50 = 0.88 μM). The most potent COX-2 inhibitors have been further investigated for their in-vivo anti-inflammatory effect. Compounds 8h , 8n , and 8p showed anti-inflammatory activity up to 90%, 94% and 86% of meloxicam after 4 h interval. 8h , 8n , and 8p showed higher gastric safety profiles than meloxicam. A substantial reduction in serum concentrations of PGE 2 , TNF-α, IL-6, iNO and MDA and a significant induction of TAC was also observed. In vivo experiments on heart rate and blood pressure established the cardiovascular safety profile of 8h , 8n , and 8p. Anti-proliferative and wild-type EGFR inhibitory assays displayed similar results to selective COX-2 inhibition where compounds 8h , 8n , and 8p had a superior inhibition than other tested ones. Molecular docking study demonstrated that these compounds revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to enter the side pocket selectively. Also, they interacted with EGFR tyrosine kinase main amino acids similar to erlotinib with a strong binding energy score. [ABSTRACT FROM AUTHOR]

• A series of novel thiazole and thiazolidenes were designed and synthesized. • Compound 6l showed potent COX-2/5-LOX inhibition. • 6l exhibited significant anti-inflammatory activity with enhanced gastric safety. • Compound 6l down regulated COX-2 and 5-LOX gene expressions efficiently. • Lead molecules could manage PGE 2 and LTB 4 levels in vitro and in vivo. Treatment of inflammation using NSAIDs is coupled with a risk of severe gastric adverse events. Development of dual COX-2/5-LOX inhibitors turns out to be an imperative area devoted to safer NSAIDs. A series of thiourea, thiazole, and thiazolidene derivatives were synthesized by green synthetic approach and COX-1, COX-2 and 5-LOX inhibition screening resulted in the identification of a potent compound 6l with IC 50 of 5.55 µM, 0.09 µM, and 0.38 µM respectively. Compound 6l made significant decrease (60.82%) in the carrageenan-induced edema in male Wistar rats. qRT-PCR analysis and determination of PGE 2 and LTB 4 in the rat paw tissues indicated that this thiazole based dual inhibitor significantly reduced the expression of COX-2 and 5-LOX genes besides the marked reduction in both PGE 2 and LTB 4 levels. The gastric safety profiling revealed an enhanced gastrointestinal safety of the compound 6l on histopathological examination. Molecular docking studies at COX-2 and 5-LOX active sites were consistent with biological studies by significant protein-ligand interaction. Besides, results of in-vitro PGE 2 and LTB 4 studies on RAW 264.7 cells as well as antioxidant studies were parallel to the dual inhibitory activity. The present investigations identify a promising lead having anti-inflammatory potential with an improved gastric safety profile. [ABSTRACT FROM AUTHOR]

• Synthesis of 23 new 4-aminosalicylate-thiazolinone hybrids. • Testing the inhibitory potencies against COX and 15-LOX and in vivo anti-inflammatory activity. • The compounds have good safety profile; they are neither cytotoxic nor ulcerogenic. • Molecular docking studies disclosed important binding modes with COX-2 and 15-LOX. Eicosanoids like leukotrienes and prostaglandins that produced within the arachidonic acid cascade are involved in the pathogenesis of pain, acute and chronic inflammatory diseases. A promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Aiming to develop balanced COX/LOX inhibitors; 4-aminosalicylate based thiazolinones having different substituents at the 5th position of the 4-thiazolinone ring (2 – 22) were designed, synthesized, characterized and evaluated in vitro and in vivo for their anti-inflammatory activity. Most of the investigated compounds showed high COX-2 inhibitory potencies (IC 50 39–200 nM) with selectivity indexes (30–84). Two compounds, 19 and 21, (IC 50 = 41 and 44 nM), are equipotent to celecoxib (IC 50 = 49 nM) , while compound 22 (IC 50 = 39 nM) was the most potent. For 15-LOX, compounds 5 , 11 , 19 , 21 and 22 revealed higher potency (IC 50 1.5–2.2 µM) than zileuton (IC 50 15 µM). Thus, compounds 5 , 11 , 1 9 , 21 and 22 are potent dual inhibitors of COX-2 and 15-LOX. In vivo anti-inflammatory testing of these compounds revealed that, compounds 5 and 21 had an anti-inflammatory activity similar to indomethacin and celecoxib (% inhibition of oedema = 60 ± 9) and higher than diclofenac potassium (% inhibition = 52 ± 29), while compound 22 (% inhibition = 63 ± 5) was more active than the reference drugs. The results showed that the activity is controlled by the bulkiness and lipophilicity of the substituent at the 5th position. The cytotoxicity results revealed that all compounds are not cytotoxic, additionally, in an experimental model of ulcerogenic effect, the most active compounds 21 and 22 showed better safety profile than indomethacin. Further, at the active sites of the COX-1, COX-2 and 15-LOX co-crystal, 19 , 21 , and 22 showed high binding forces in free binding energy study, which is consistent with in vitro and in vivo results. In conclusion, these compounds are good candidates for further biological investigation as potential anti-inflammatory drugs with dual balanced inhibition of COX and 15-LOX and good safety profile. [ABSTRACT FROM AUTHOR]

Endocannabinoids appear to be involved in a variety of physiological processes. Lipoxygenase activity has been known to be affected by unsaturated fatty acids or phenolic compounds. In this study, we examined whether endocannabinoids containing both N-acyl group and phenolic group can affect the activity of soybean lipoxygenase (LOX)-1, similar to mammalian 15-lipoxygenase in physicochemical properties. First, N-arachidonoyl dopamine and N-oleoyl dopamine were found to inhibit soybean LOX-1-catalyzed oxygenation of linoleic acid in a non-competitive manner with a Ki value of 3.7 μM and 6.2 μM, respectively. Meanwhile, other endocannabinoids failed to show a remarkable inhibition of soybean LOX-1. Separately, N-arachidonoyl dopamine and N-arachidonoyl serotonin were observed to inactivate soybean LOX-1 with Kin value of 27 μM and 24 μM, respectively, and k3 value of 0.12 min(-1) and 0.35 min(-1), respectively. Furthermore, such an inactivation was enhanced by ascorbic acid, but suppressed by 13(S)-hydroperoxy-9,11-octadecadienoic acid. Taken together, it is proposed that endocannabinoids containing polyunsaturated acyl moiety and phenolic group may be efficient for the inhibition as well as inactivation of 15-lipoxygenase., (Copyright © 2013 Elsevier Inc. All rights reserved.)