Preclinical Development of Pentamidine Analogs Identifies a Potent and Nontoxic Antibiotic Adjuvant was written by MacNair, Craig R.;Farha, Maya A.;Serrano-Wu, Michael H.;Lee, Katie K.;Hubbard, Brian;Cote, Jean-Philippe;Carfrae, Lindsey A.;Tu, Megan M.;Gaulin, Jeffrey L.;Hunt, Diana K.;Hung, Deborah T.;Brown, Eric D.. And the article was included in ACS Infectious Diseases in 2022.Safety of (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-25-(Acetyloxy)-5,6,21,23-tetrahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]benzimidazole-1,15(2H)-dione This article mentions the following:
The difficulty in treating Gram-neg. bacteria can largely be attributed to their highly impermeable outer membrane (OM), which serves as a barrier to many otherwise active antibiotics. This can be overcome with the use of perturbant mols., which disrupt OM integrity and sensitize Gram-neg. bacteria to many clin. available Gram-pos.-active antibiotics. Although many new perturbants have been identified in recent years, most of these mols. are impeded by toxicity due to the similarities between pathogen and host cell membranes. For example, our group recently reported the cryptic OM-perturbing activity of the antiprotozoal drug pentamidine. Its development as an antibiotic adjuvant is limited, however, by toxicity concerns. Herein, we took a medicinal chem. approach to develop novel analogs of pentamidine, aiming to improve its OM activity while reducing its off-target toxicity. We identified the compound P35 (I), which induces OM disruption and potentiates Gram-pos.-active antibiotics in Acinetobacter baumannii and Klebsiella pneumoniae. Relative to pentamidine, P35 has reduced mammalian cell cytotoxicity and hERG trafficking inhibition. Addnl., P35 outperforms pentamidine in a murine model of A. baumannii bacteremia. Together, this preclin. anal. supports P35 as a promising lead for further development as an OM perturbant. In the experiment, the researchers used many compounds, for example, (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-25-(Acetyloxy)-5,6,21,23-tetrahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]benzimidazole-1,15(2H)-dione (cas: 80621-81-4Safety of (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-25-(Acetyloxy)-5,6,21,23-tetrahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]benzimidazole-1,15(2H)-dione).
(2S,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-25-(Acetyloxy)-5,6,21,23-tetrahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]benzimidazole-1,15(2H)-dione (cas: 80621-81-4) belongs to benzofurans derivatives. Benzofuran derivatives have shown many biological activities, including antifungal and antimicrobial properties, and acting as antagonists of H3 receptors and angiotensin II. Benzofurans have also made significant and distinctive contributions to biology. They exhibit several biological activities that range from antioxidant, antitubercular, antiplasmodial, insecticidal.Safety of (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-25-(Acetyloxy)-5,6,21,23-tetrahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]benzimidazole-1,15(2H)-dione
Referemce:
Benzofuran – Wikipedia,
Benzofuran | C8H6O – PubChem