Divergent Chemo- and Biocatalytic Route to 16ß-Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate.

16ß-Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16ß-methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability-oriented strategy toward the unified stereoselective synthesis of 16ß-methylcorticoids in 12.6-14.0 % overall yield from commercially available 9α-hydroxyandrost-4-ene-3,17-dione (9α-OH-AD). In this approach, the chiral C16ß-Me and C17α-OH groups of the corticosteroid D ring were installed via a substrate-controlled diastereo- and enantioselective Mn-catalyzed oxidation-reduction hydration of Δ4,9(11),16 -triene-3,20-dione. The C1-C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3-ketosteroid-Δ1 -dehydrogenase (MK4-KstD)-catalyzed regioselective Δ1 -dehydrogenation of Δ4,9(11) -diene-3,21-dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.

Optimization of P2Y12 Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties.

P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.

Design, synthesis, and structure-activity relationship studies of novel tetrazole antifungal agents with potent activity, broad antifungal spectrum and high selectivity.

In this letter, we report our efforts to design, synthesize and evaluate biological activities of a series of novel hybridized compounds containing 1-tetrazole and 4-pyridinyl-1,2,4-triazole-3-one. An analysis of structure-activity data indicates that the target compounds with bulky and hydrophobic side chains exhibited stronger activities against the Candida spp and Cryptococcus neoformans tested than those of fluconazole and racemic VT-1161. Furthermore, 13k and 13ad were active against Microsporum gypseum, which was resistant to racemic VT-1161. In addition, 13k, 13ac and 13ad, with good in vitro activities against all of pathogenic fungi tested except for Aspergillus fumigatus, had no inhibition of human CYP3A4, suggesting a low risk of drug-drug interactions.

New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment.

The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor's extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N-formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors.