RESUMEN
The synthesis and antibacterial activity in vitro of 7-(2-heteroarylacetamido)-3-[(2,3- cyclopentenopyridinium)methyl]cephalosporins and of some related compounds with different ammonium functions in 3'-position are described. The 7-[5-amino-1,2,4-thiadiazol-3-yl] and the 7-[4-aminopyrimidin-2-yl] analogues of cefpirome and compounds with 3-aliphatic ammoniummethyl functions have excellent antibacterial activity. Cephalosporins with different N-heterocycles other than pyridine in 3'-position are less active than their 3-pyridiniummethyl analogues. Attachment of a pyridinium group to a cephem at C-3 via a thiomethyl or an aminomethyl bridge causes reduction of antibacterial activity.
Asunto(s)
Cefalosporinas/síntesis química , Cefalosporinas/farmacología , Fenómenos Químicos , Química , Enterobacter/efectos de los fármacos , Klebsiella/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Pseudomonas/efectos de los fármacos , Streptococcus/efectos de los fármacos , Relación Estructura-Actividad , CefpiromaRESUMEN
7 alpha-Methoxy and 7 alpha-formamido derivatives of cefpirome (HR 810) have been synthesized and tested in comparison with cefpirome and some analogues 1 against aerobic and anaerobic bacteria. Cefpirome and analogues 1 have good activity against Gram-positive and only limited activity against Gram-negative anaerobic bacteria. 7 alpha-Methoxy derivatives 2 show only a slight improvement of activity against Gram-negative anaerobes and are less active against all aerobes. Introduction of the 7 alpha-formamido group (compounds 3) results in an overall loss of activity towards both aerobic and anaerobic bacteria.
Asunto(s)
Cefalosporinas/síntesis química , Cefalosporinas/farmacología , Fenómenos Químicos , Química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Relación Estructura-Actividad , CefpiromaRESUMEN
7-[2-(2-Aminothiazol-4-yl)-2-(Z)-oxyiminoacetamido]-3-[(s ubs tituted-1-pyridinio)methyl]ceph-3-em-4-carboxylates II are a group of beta-lactam antibiotics with extraordinary high antibacterial activity. The promising member of this group, cefpirome (HR 810, II-1) is a candidate for clinical use. Synthetic pathways to II starting from cefotaxime derivatives I or 7-aminocephalosporanic acid (7-ACA) are described. A preferred method for the conversion of I to II or 7-ACA to precursors III respectively employs iodotrimethylsilane and an excess of the pyridine base. Structure-activity studies reveal an optimum overall activity in the series of pyridines with fused saturated and unsaturated rings or cyclopropyl- and alkoxy substituents. Favorable oxyimino substituents are methyl, ethyl, difluoromethyl and carbamoylmethyl groups. Acidic substituents lead to decreased activity against Staphylococcus aureus SG 511. Introduction of halogen in the thiazole nucleus causes improvement of activity against the K1 beta-lactamase producing Klebsiella aerogenes 1082 E strain.