Synthesis and Evaluation of a New Series of 3,5‐bis((5‐bromo‐6‐methyl‐2‐t‐aminopyrimidin‐4‐yl)thio)‐4H‐1,2,4‐triazol‐4‐amines and their Cyclized Products ‘Pyrimidinylthio Pyrimidotriazolothiadiazines’ as 15‐ Lipo‐Oxygenase Inhibitors

Abstract

A series of new 3,5-bis((5-bromo-6-methyl-2-t-aminopyrimidin-4-yl)thio)-4H-1,2,4-triazol-4-amines and their cyclized products 'pyrimidinylthio pyrimidotriazolothiadiazines' were designed, synthesized, and evaluated as potential inhibitors of 15-lipo-oxygenase (15-LO). Their syntheses started by initial condensation of 2:1 equivalents of pyrimidine with triazole and subsequent nucleophilic displacement of the chlorine atoms with secondary amines and finally cyclocondensation in the presence of NaNH2. The compounds 4d and 4f showed the best IC50 of 15-LO inhibition (IC50 = 9 and 12 μm, respectively). Compounds 4a-g were docked into 15-LO. We suggest that the hydrogen bonds in quaternary nitrogen of piperazine ring of compounds 4d and 4f appear to play major role in lipo-oxygenase inhibition by this set of synthesized analogs and hydrophobic nature of this protein's binding site should be considered in ongoing investigations.

Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties

“…Furthermore, five-membered heterocycles like pyrazole-based sulfonamide and sulfamides (IC 50 = 1.4 nM, r12/15-LOX),23 oxadiazole or oxazole derivatives as ML094 (IC 50 = 10 nM, h-15-LOX-1)24 and ML351 (IC 50 = 200 nM, h-15-LOX-1)25 but also imidazole-based compounds (IC 50 = 75 nM, r12/15-LOX)26 are reported as 15-LOX inhibitors. In addition, indolizine (IC 50 = 25 μM, r12/15-LOX),27 thiourea-based (IC 50 = 1.8 μM, soybean 15-LOX)28 and thiadiazine (IC 50 = 9 μM, soybean 15-LOX)29 derivatives were developed as 15-LOX inhibitors, although they demonstrate a relatively low inhibitory potency. Recently, anacardic acid derived salicylates were described by our research group as LOX inhibitors 30–32.…”

Synthesis of New Pyrimido[4,5‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine Derivatives via S/N Smiles Rearrangement

“…Based on these findings and in continuation of our studies on the synthesis of potentially bioactive heterocyclic compounds , we wish to report on the synthesis and regiochemistry of new pyrimido[4,5‐ e ][1,2,4]triazolo[3,4‐ b ][1,3,4]thiadiazine derivatives.…”

Synthesis of New Derivatives of 4‐(4,7,7‐Trimethyl‐7,8‐dihydro‐6H‐benzo[b]pyrimido[5,4‐e][1,4]thiazin‐2‐yl)morpholine

“…In view of the aforementioned facts and also in continuation of our research program on the synthesis of new heterocyclic compounds [18,24,25], in this study, we wish to report on the synthesis of new derivatives of benzo [b]pyrimido [5,4-e] [1,4]thiazin-2-yl) morpholine.…”