Design, synthesis and biological evaluation of novel desmuramyldipeptide analogs

A series of novel desmuramyldipeptides have been designed and synthesized as part of our search for therapeutically useful muramyldipeptide (MDP) analogs. Their immunomodulatory properties were initially assessed in vitro, evaluating their effect on lipopolysaccharide (LPS)-induced cytokine release in THP-1 cells. Following the initial screening, selected compounds were further investigated for immunomodulatory properties using LPS and phorbol 12-myristate 13-acetate (PMA)/ionomycin-stimulated human peripheral blood mononuclear cells. The results confirmed the immunomodulatory properties of some of the synthesized desmuramyldipeptide analogs. Taken together, presented data confirmed the immunostimulatory effect of compound 44, MDP derivative incorporating a pyrido-fused [1,2]-benzisothiazole moiety, while for compounds 32 and 39, indole scaffold-based derivatives of MDP, an immunosuppressive effect was observed. Further studies will be necessary to address their potential therapeutic use as immunomodulatory drugs, both as immunostimulants or anti-inflammatory agents. [Display omitted] ► Design and synthesis of novel desmuramyldipeptides. ► The immunomodulatory properties were measured by employing THP-1 cells and PBMCs. ► Some of indole scaffold-based MDP analogs decreased proinflammatory cytokine synthesis. ► Pyrido-fused [1,2]-benzisothiazole derivative showed immunostimulant activity.