Antibacterial activity and pharmacokinetics of four new 7-azetidinyl fluoroquinolones

Abstract

The activity of E-4535, E-4534, E-4528, and E-4527, four new 7-azetidinyl-6-fluoroquinolones, was studied to evaluate the role played by the C-2' and C-3' substitutions of the azetidinyl group, together with a C-8 fluorine atom. In general, like other 6,8-difluoroquinolones, E-4534 and E-4527 showed higher levels of activity than the corresponding monofluorinated derivatives, E-4535 and E-4528. E-4535 and E-4534, having a 7-(2-methyl-3-aminoazetidinyl) substituent, demonstrated higher levels of activity in vitro than their corresponding structural analogs, E-4528 and E-4527, distinguished by a 3-methyl-3-methylaminoazetidinyl group at position 7 of the quinolone nucleus. In consequence, E-4534 was the most potent of the new agents tested.

Killing of Staphylococcus aureus by C-8-Methoxy Fluoroquinolones

“…A computational approach indicated that C-8 fluorine or alkoxy groups, when coupled with an N-1 cyclopropyl moiety, would increase bacteriostatic activity (15). This was the case for 15 of 16 bacterial species subsequently tested (4). Another study showed that a C-8 chlorine increased activity against Pseudomonas aeruginosa, especially with strains containing a quinolone-resistant gyrase (14).…”

Quinolonas: Aspectos generales sobre su estructura y clasificación

“…15 Un caso especial lo constituye grepafloxacina (OPC 17116) antimicrobiano recientemente retirado del mercado farmaceútico por fenómenos de cardiotoxicidad derivados de su uso. 26 Otras quinolonas con ciclopropil como sustituyente en N1 son balofloxacina (Q-35) (también discontinuada), 27 CS-940, 28 las quinolonas desarrolladas por Laboratorios Esteve de España E-3846, 29 E-4884, E-4874, 30 E-4502, E-4501, E-4500, E-4474, E-4480, E-4441, 31 E-4695, 32 E-4535, E-4527, E-4528, E-4534, 33 E-5065, 34 gatifloxacina (AM 1155, CG 5501), 35 AM-1091, 36 A-60919, 15 CI-990, PD 131112, 22 CI-938, 15 moxifloxacina (BAY 12-8039), 16 MF 5137, 16 sitafloxacina (DU-6859a). 37 El ciclopropil combina favorables propiedades estéricas, espaciales y de interacción electrónica, así la quinolona de mayor uso clínico, ciprofloxacina, presenta un grupo ciclopropil a nivel N1, exhibiendo una potente actividad sobre enterobacterias y Pseudomonas aeruginosa.…”

“…11 La presencia de un grupo azetidina en la posición 7 tiene resultados variables en la actividad del antimicrobiano, así las moléculas más pequeñas y por tanto con menos sustituyentes exhiben una modesta actividad comparada con ciprofloxacina, mientras que moléculas mayores presentan una actividad comparable e incluso superior a la de ciprofloxacina, particularmente sobre especies Gram positivas. [29][30][31][32][33][34]42…”

Novelties in the field of fluoroquinolones

“…It has an identical activity to ciprofloxacin against Enterobacteriaceae, and is slightly more active than levofloxacin. It is less active than ciprofloxacin against P. aeruginosa (Table 11) [36]. In vivo, in systemic infections, it is more active than ciprofloxacin against S. aureus HS-93, E. coli HM 42 and P. aeruginosa HS-46.…”