Design, development and evaluation of a prodrug-type TrkA-selective inhibitor with antinociceptive effects in vivo.

Tropomyosin receptor kinase A (TrkA) is considered a therapeutic target in pain treatment, and several TrkA inhibitors have been designed and developed as potential analgesics. The subselectivity toward TrkA is closely associated with safety and efficacy and was achieved by developing an allosteric inhibitor to occupy the less conserved non-ATP binding site. Druggable modifications of potent TrkA inhibitors could be challenging due to the unique requirement of functional groups that supply potency but are accompanied by poor druggability. We developed carboxyl acid 5 as a potent (IC50 = 22.4 nM) and subselective TrkA inhibitor (>8000-fold toward TrkB and TrkC). We also converted 5 to corresponding prodrug 39 as a useful tool compound in future analgesic development with promising antinociceptive effects in both hot plate testing and formalin-induced pain models with a suitable ED50 value (7.8 mg/kg).

Iron-catalyzed radical cascade cyclization of oxime esters with isocyanides: synthesis of 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines.

An iron-catalyzed radical cascade cyclization of oxime esters with isocyanides for the synthesis of 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines has been developed. This demonstrates excellent functional group tolerance and broad substrate scope. A diverse range of potentially valuable 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines were obtained in moderate to good yields.

Design, synthesis and evaluation of carbazole derivatives as potential antimicrobial agents.

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5-2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure-activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.

Additive-Free Radical Cascade Reaction of Oxime Esters: Synthesis of Pyrroline-Functionalized Phenanthridines.

A variety of dihydropyrrole-functionalized phenanthridines were efficiently synthesized by the metal-free, radical cascade cyclization reaction of 2-isocyanobiphenyls with γ,δ-unsaturated oxime esters. The C-N/C-C/C-C bonds were formed via the oil bath method in a one-pot procedure with broad substrate applicability. The radical process was supported by kinetic isotope effect studies and radical inhibition studies.

Synthesis and Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as TGF-ß Type I Receptor Kinase Inhibitors.

The transforming growth factor-ß (TGF-ß), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a⁻d, 15a⁻d, 16a⁻d, 17a⁻d, 18a⁻d, 19a⁻d, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d were synthesized and evaluated for their activin TGF-ß type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound 19b inhibited TGF-ß type I receptor kinase phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 19b also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.