Exploration of 1,2,3-triazolo fused triterpenoids as inhibitors of human coronavirus 229E targeting the viral nsp15 protein.

The coronavirus disease-19 (COVID-19) pandemic has raised major interest in innovative drug concepts to suppress human coronavirus (HCoV) infections. We previously reported on a class of 1,2,3-triazolo fused betulonic acid derivatives causing strong inhibition of HCoV-229E replication via the viral nsp15 protein, which is proposedly related to compound binding at an intermonomer interface in hexameric nsp15. In the present study, we further explored the structure-activity relationship (SAR), by varying the substituent at the 1,2,3-triazolo ring as well as the triterpenoid skeleton. The 1,2,3-triazolo fused triterpenoids were synthesized by a multicomponent triazolization reaction, which has been developed in-house. Several analogs possessing a betulin, oleanolic acid, or ursolic acid core displayed favorable activity and selectivity (EC50 values for HCoV-229E: 1.6-3.5 µM), but neither of them proved as effective as the lead compound containing betulonic acid. The 18ß-glycyrrhetinic acid-containing analogs had low selectivity. The antiviral findings were rationalized by in silico docking in the available structure of the HCoV-229E nsp15 protein. The new SAR insights will aid the further development of these 1,2,3-triazolo fused triterpenoid compounds as a unique type of coronavirus inhibitors.

Oxidative carbonylation of N-protected indoles by Rh(III)-zeolites.

The oxidative carbonylation of N-protected indoles was investigated to directly synthesize indole-3-carboxylic acids. Using Rh(III)-zeolites as heterogeneous catalysts, the single-site Rh-species reach unprecedented activities (>100 turnovers), while the metal is readily recovered after reaction. X-ray absorption spectroscopy (XAS) provided evidence for site-isolation of Rh(III) species on the zeolite.

Triphenylphosphonium-linked derivative of allobetulin: preparation, anticancer properties and their mechanism of inhibiting SGC-7901 cells proliferation.

As a very important lipophilic cation, the triphenylphosphonium moiety has been extensively studied in the development of anticancer agents. In this work, we adopted 1,2,3-triazole as the linking group to prepare triphenylphosphine salt-natural triterpenoid conjugates. We chose the rarely studied natural triterpenoid allobetulin as the lead compound and prepared three 1,2,3-triazole derivatives of allobetulin by the triazolization reaction which was developed by our group. The hydroxyl group was then replaced by bromination, and the target triphenylphosphonium-linked derivative of allobetulin 5 was obtained by reacting with triphenylphosphine. The cytotoxicity screening showed that the target compound 5 displayed same antiproliferative activity against tested cancer cells as the commercial anticancer drug doxorubicin but more active than cisplatin. Further studies on the mechanism of action indicated that compound 5 could obviously induce SGC-7901 cells apoptosis through the mitochondrial pathway, inducing cell cycle arrest. Moreover, compound 5 also could reduce the expression of Vimentin and increase the expression of E-cadherin to hinder Epithelial-mesenchymal transition (EMT). Since compound 5 has excellent anticancer activity, further research and development should be done.

Antibacterial and antitumoral properties of 1,2,3-triazolo fused triterpenes and their mechanism of inhibiting the proliferation of HL-60 cells.

Antimicrobial resistance and cancer are two important problems affecting human health. Actively developing novel antibiotics and anticancer medicines is a priority. Natural pentacyclic triterpenoids have attracted wide attention due to their significant biological activities. In this study, a series of 1,2,3-triazolo fused triterpenoids (betulin, oleanolic acid and ursolic acid) were functionalized on the A-ring by an in-house developed multi-component triazolization reaction. The compounds were investigated for antitumoral activity in twelve cancer cell lines and were also tested for antibacterial activity against four bacteria. In terms of anticancer effects, compounds 5b-f and 8a-d displayed strong cytotoxic activity in pancreatic adenocarcinoma (Capan-1), chronic myeloid leukemia (Hap-1), acute myeloid leukemia (HL-60), acute lymphoblastic leukemia (Jurkat) and non-Hodgkin lymphoma (Rec-1) cell lines. Among them, compound 5f exhibited the most potent antiproliferative effect on HL-60 cells. Further pharmacological research confirmed that compound 5f caused mitochondrial dysfunction and arrested the cell cycle in the G0/G1 phase to induce apoptosis of HL-60 cells. In addition, compound 5f also induced autophagy to inhibit the proliferation of HL-60 cells. Antibacterial screening revealed that compounds 2a-g and 5a-d showed modest activity against Gram-negative bacteria (Escherichia coli and Salmonella enterica subsp. enterica) with especially compounds 2c and 2d being potent inhibitors of Salmonella enterica subsp. enterica growth. Because of their promising anticancer and antibacterial activity, this series of compounds deserve further study.

Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease.

To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC50: 0.6 µM) of HCoV-229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of HCoV-229E nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.

Synthesis of 1,2,3-Triazolo-Fused Allocolchicine Analogs via Intramolecular Oxidative Biaryl Coupling.

A novel series of 1,2,3-triazolo-fused allocolchicine analogs is described. The strategy to prepare these analogs involves two steps: The first step is the synthesis of 1,2,3-triazole derivatives using our previously reported triazolization method, and in the second step, cyclization between two aromatic rings occurs by using the combination of PIFA and BF3·Et2O as an oxidative coupling reagent. Furthermore, the diversity of aromatic rings and functional groups is explored in order to obtain seven- and eight-membered ring systems with medicinal chemistry interest.

General Transition Metal-Free Synthesis of NH-Pyrroles from Secondary Alcohols and 2-Aminoalcohols.

A novel, transition metal-free and one-pot methodology to synthesize various substituted NH-pyrroles from readily available building blocks such as secondary alcohols and 2-aminoalcohols is described. The process is based on the venerable Oppenauer-Woodward oxidation, which uses benzophenone as an inexpensive reagent to achieve oxidation of secondary alcohols under mild condition to ketones, further in situ condensation with aminoalcohol, and oxidative cyclization to the target pyrrole ring. The reaction occurs under basic conditions, and features a broad substrate scope combined with very good tolerance for sensitive functional groups. This method can be used to synthesize various substituted pyrroles useful as a starting material for broad applications.