N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

Abstract

Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10 000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC and a 1.7-fold improvement in brain AUC with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical properties and enhanced bioavailability in both mice and dog.

A series of Mn(i) photo-activated carbon monoxide-releasing molecules with benzimidazole coligands: synthesis, structural characterization, CO releasing properties and biological activity evaluation

“…The pyridine ring H signals appeared at 8.03-9.26 ppm and the BIM proton signals appeared at 7.24-8.15 ppm, which are corresponding with those of the complexes reported in literatures 35,36. All complexes are diamagnetic as evidenced by clean 1 H NMR spectra in solvents, which ensures that only Mn(I) is present.…”

Continuous flow synthesis of diaryl ketones by coupling of aryl Grignard reagents with acyl chlorides under mild conditions in the ecofriendly solvent 2-methyltetrahydrofuran

“…[1][2][3] They exist in numerous bioactive molecules ( Fig. 1), 1,4 such as the nonsteroidal anti-inammatory drug (NSAID) ketoprofen, 5 the broad-spectrum human anthelmintic mebendazole, 6 the classical lipid regulating agent feno-brate 7 and the therapeutically useful uricosuric agent benzbromarone (BBR) 8 (Fig. 1).…”

Aldehydes: magnificent acyl equivalents for direct acylation

“…In 2014, Li and co-workers disclosed a metal-free protocol for the acylation of N-arylacrylamides with aldehdyes followed by an intramolecular cyclization to synthesize 3acylspiro [4,5]trienones. 73 The flexibility of reaction was demonstrated by the synthesis of 28 3-acylspiro [4,5]trienones in good to excellent yields.…”

“…In 2014, Li and co-workers disclosed a metal-free protocol for the acylation of N-arylacrylamides with aldehdyes followed by an intramolecular cyclization to synthesize 3acylspiro [4,5]trienones. 73 The flexibility of reaction was demonstrated by the synthesis of 28 3-acylspiro [4,5]trienones in good to excellent yields. Reactions were performed between several electron-rich and electron-deficient Narylacrylamides and aldehydes (aromatic and aliphatic) using TBHP as optimum free-radical initiator oxidant without any catalyst under optimized reaction conditions giving the respective products in 66-94% yield.…”

“…These are the fundamental building blocks of various bioactive molecules and drugs such as tiaprofenic acid and ketoprofen which are used as anti-photoallergic agents 1 and nonsteroidal antiinflammatory drugs, 2 fenofibrate that is used as the classical lipid regulating agent 3 , benzbromarone (BBR) which is employed as a uricosuric agent 4 , and mebendazole that works as a broad-spectrum human anthelmintic agent. 5 Over the course of time, structural diversity of the disubstituted ketone moieties has rapidly expanded as evident from the literature reports. However, the practical challenges associated with the conventional methodologies employed for the synthesis of these significant motifs have in turn engaged the researchers in exploration of improved methods of synthesis.…”