Identification of multi-target inhibitors of leukotriene and prostaglandin E2 biosynthesis by structural tuning of the FLAP inhibitor BRP-7

Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions

“…Thus, the developed optimised protocol was successfully applied for the flow synthesis of N -(2-chlorobenzyl)-5-cyano-benzimidazol-2-one ( 3 ), which is a key synthon for hit-to-lead exploration in anti-inflammatory drug discovery targeting 5-lipoxygenase-activating protein (FLAP) (Figure 4) [26,32]. In this regard, N -substituted o -phenylenediamine 4 , which was used as the starting material, was synthesised under conventional batch conditions by the reaction of the corresponding o -phenylenediamine with 2-chlorobenzyl bromide, as previously reported [22,36].…”

“…: 234–235 °C, lit. [26]: 233.9–234.9 °C). 1 H-NMR (400 MHz, CDCl 3 ): δ 5.24 (s, 2H), 6.93 (d, J = 8.2 Hz, 1H), 7.08 (dd, J 1 = 8.0 Hz, J 2 = 1.6 Hz, 1H), 7.17–7.22 (m, 1H), 7.24-7.28 (m, 1H), 7.33 (dd, J 1 = 8.2 Hz, J 2 = 1.4 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 7.43 (dd, J 1 = 8.0 Hz, J 2 = 1.6 Hz, 1H), 8.09 (s, 1H).…”

“…Following our interest in benzimidazole-based drug discovery [22,23,24,25,26] and in the application of flow technology in medicinal chemistry programs [27,28,29,30], in this paper, we report a novel flow synthesis of benzimidazol-2-one ( 1 ) by the CDI-promoted cyclocarbonylation of o -phenylenediamine ( 2 ). In particular, with the aim to set up a general method for enabling an efficient multigram-scale preparation of key synthons for hit-to-lead explorations, we applied the following workflow: (i) batch screening of the model reaction, (ii) translation under flow conditions and optimisation by statistical design of experiment (DoE) [31], and (iii) application of the optimised protocol for the gram-scale flow synthesis of N -(2-chlorobenzyl)-5-cyano-benzimidazol-2-one ( 3 ), which will be used in our medicinal chemistry efforts towards anti-inflammatory drug discovery targeting 5-lipoxygenase-activating protein (FLAP) [26,32].…”

Synthesis, in silico studies and cytotoxicity evaluation of novel 1,3,4-oxadiazole derivatives designed as potential mPGES-1 inhibitors

“…The compound with new thioether scaffold like our newly synthesized compounds inhibits mPGES-1 enzyme at the concentration of 9.3 nM in cell free assay and 0.7 µM in human whole blood assay [21]. Although it is known that 1,3,4-oxadiazole derivates can show anti-inflammatory potency (10), to our knowledge only one compound containing 1,3,4-oxadiazole scaffold showed inhibitory effect against mPGES-1 at 0.42 µM [48]. Herein this study we report the identification of a new type of inhibitors combining both 1,3,4-oxadiazole and thioether groups through both computational and experimental studies ( Figure 2).…”

Ethoxy acetalated dextran-based nanocarriers accomplish efficient inhibition of leukotriene formation by a novel FLAP antagonist in human leukocytes and blood

“…Thus, FLAP assists 5-lipoxygenase (5-LO) in the generation of leukotrienes (LTs) that display potent chemotactic effects, activate pro-inflammatory leukocytes and constrict small vessels, while mPGES-1 catalyzes the transformation of cyclooxygenase-derived prostaglandin (PG)H 2 to PGE 2 that mediates pain and fever, and increases the vascular permeability [ 2 , 3 ]. Our previous structure–activity relationship studies on benzimidazole-based dual inhibitors of FLAP and mPGES-1 revealed BRP-201 (5-{1-[(2-chlorophenyl)methyl]-2-{1-[4-(2-methylpropyl)phenyl]ethyl}-1H-benzimidazole-5-yl}-2,3-dihydro-1,3,4-oxadiazole-2-thione) as the most potent derivative [ 4 ]. However, BRP-201 and many other structurally different dual mPGES-1/FLAP inhibitors or FLAP antagonists suffer from loss of efficiency in biological/pharmacological relevant environments apparently due to strong unspecific protein binding based on their acidic and lipophilic structures [ 1 , 5 ].…”