SYNTHESIS, HYDROLYTIC STABILITY AND ANTIVIRAL STUDIES OF SULFUR-BASED ANTI-INFLUENZA DRUGS

Sulfur - containing building blocks represent highly favored scaffolds in various natural or synthetically obtained pharmacologically active molecules. Their diverse functionalities, including thioether, sulfonamide, sulfoxide, and others are often linked with the possibility to inhibit microbial growth and to regulate immune responses. Nowadays, approximately 25 % of all utilized small - molecule pharmaceuticals have been approved as organosulfur drugs or are clinical candidates. Herein, inspired by the medicinal power of such compounds, a series of potential sulfur based ligands against influenza A viruses was obtained by modification of amino group of anti - influenza drugs (rimantadine, amantadine and oseltamivir) and memantine. Furthermore, the structures of novel derivatives bearingversatile sulfur - containing acyl moieties (cysteinyl-, thienyl-) were established by spectroscopic methods (1H NMR, 13C NMR, (ATR)umax, and HRMS). The newly synthesized amides were tested in vitro for antiviral activity against four influenza A viruses (A/Fort Monmouth/1/1947 (H1N1), A/Wuhan/359/1995 (H3N2), A/Jinnan/15/2009 (H1N1), and A/Aichi/2/68 (H3N2). Amongst the evaluated amides 1, 6, and 7 were the most active ones, inhibiting both the A/Fort Monmouth/1/1947 (H1N1) and A/Wuhan/359/1995 (H3N2) influenza virus strains, while amides 3 and 5 showed pronounced antiviral efficacy specifically against the A/Wuhan/359/1995 (H3N2) strain. Moreover, compounds 6 and 7 indicated remarkable inhibitory activity against the oseltamivir-resistant A/Jinnan/15/2009 strain.Furthermore, the hydrolytic stability of desired amides was monitored in two model pH systems that mimic conditions in the stomach, and blood plasma, including pH 1.0, and 7.4, respectively.