Discovery of Novel Ureas and Thioureas of 3-Decladinosyl-3-hydroxy 15-Membered Azalides Active Against Efflux-mediated Resistant Streptococcus. Pneumoniae

Abstract A series of novel ureas and thioureas of 3-decladinosyl-3-hydroxy 15-membered azalides, were discovered, structurally characterized and biologically evaluated. They have shown good antibacterial activity against selected Gram-positive and Gram-negative bacterial strains. These include N″ substituted 9a-( N ′-carbamoyl-γ-aminopropyl)- ( 6a , c ), 9a-( N ′-thiocarbamoyl-γ-aminopropyl)- ( 7a , e ), 9a-[ N ′-(β-cyanoethyl)- N ′-(carbamoyl-γ-aminopropyl)]- ( 9a – c , 9g) 9a-[ N ′-(β-cyanoethyl)- N ′-(thiocarbamoyl-γ-aminopropyl)]-derivatives ( 10d – f ) of 5- O -desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A ( 3 ). Among the synthesized compounds thiourea 7a and urea 9b have shown substantially improved activity comparable to azithromycin ( 1 ) and significantly better activity than the 3-decladinosyl-azithromycin ( 2 ) and the parent 3-cladinosyl analogues against efflux-mediated resistant S. pneumoniae .