Stereoselective Synthesis of Baloxavir Marboxil Using Diastereoselective Cyclization and Photoredox Decarboxylation of l-Serine.

Baloxavir marboxil (1; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM (1) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM (1). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core ((R)-14). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.

Design, Synthesis, and Anti-Inflammatory Evaluation of a Novel PPARδ Agonist with a 4-(1-Pyrrolidinyl)piperidine Structure.

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ agonist activity (EC50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir.

We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the development of a concise and efficient scale-up process to Ensitrelvir. In this process, introducing a meta-cresolyl moiety successfully enhanced the stability of intermediates. Compared to the initial route at the early research and development stage, the overall yield of the longest linear sequence (6 steps) was improved by approximately 7-fold. Furthermore, 9 out of the 12 isolated intermediates were crystallized directly from each reaction mixture without any extractive workup (direct isolation). This led to an efficient and environmentally friendly manufacturing process that minimizes waste of organic solvents, reagents, and processing time. This practical process for manufacturing Ensitrelvir should contribute to protection against COVID-19.

Discovery and structure-activity relationship study of 2-piperazinyl-benzothiazole derivatives as potent and selective PPARδ agonists.

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a target for treating metabolic syndrome, whereas there is no PPARδ agonist in clinical use. Previously, we have reported the discovery of 2-(1-piperidinyl)-1,3-benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening techniques. In this study, we performed the further optimization study of the lead compound 1 focusing on improvement of hydrophobic interactions in the binding site to enhance agonist efficacy for PPARδ and subtype selectivity, thereby discovering a novel PPARδ agonist 5g which exhibited high in vitro agonist activity (hPPARδ, EC50 = 4.1 nM) and sufficiently high selectivity ratio over PPARα and PPARγ. Moreover, 5g revealed a significant upregulation of high-density lipoprotein cholesterol level in vivo.

Discovery and structure-based design of a new series of potent and selective PPARδ agonists utilizing a virtual screening method.

Novel PPARδ agonists, 2-(1-piperidinyl)-1,3-benzothiazole derivatives were discovered by our proprietary docking-based virtual screening technique. Compound 1 as the initial hit was effectively modified to acquire PPARδ agonist activity, resulting in the discovery of compound 12 with high agonistic potency for PPARδ and selectivity over PPARα and PPARγ. Compound 12 also had good ADME profiles and showed in vivo efficacy as a lead.

Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases.

5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.

Synthesis and evaluation of novel pyrimidine-based dual EGFR/Her-2 inhibitors.

A structure-activity relationship study of 4-anilinopyrimidines for dual EGFR/Her-2 inhibitor has resulted in the identification of 4-anilino-5-alkenyl or 5-alkynyl-6-methylpyrimidine derivatives that have exhibited effective inhibitory activity against both enzymes. The presence of 5-alkenyl or 5-alkynyl moiety bearing terminal hydrophilic group played important role for inhibition of these enzymes. Selected compounds in the series demonstrated some activity against Her-2 dependent cell line (BT474).

Towards the synthesis of a Yersinia pestis cell wall polysaccharide: enantioselective synthesis of an L-glycero-D-manno-heptose building block.

A short and enantioselective de novo synthesis of an L-glycero-D-manno-heptose building block for the total synthesis of a Yersinia pestis cell wall polysaccharide is described.

Novel antibacterial macrolides: synthesis of 15-membered diolides.

Novel 15-membered macrolides possessing the dilactone skeleton, diolides 13a and 13b, have been synthesized in our research program aimed at finding new antibacterial macrolides. Key strategic elements of the approach include the ring-expanding reaction of 13-membered dilactones, prepared from erythromycin A (Ery-A), to 15-membered dilactones via intramolecular translactonization. The absolute configuration at the regenerated C-8 position of the new diolides was determined by chemical transformation, leading to the corresponding lactam analogues, whose stereochemistry is known in the literature. For further confirmation, X-ray analysis was performed. The X-ray structure determination of 13a revealed a backbone conformation similar to that of Ery-A. Novel 15-membered diolide 13a and the 11,12-diol 18 exhibited antibacterial activities comparable to that of Ery-A.