Coupling Reactions of Cephalosporin Sulfones: A Stable 3-Stannylated Cephem (original) (raw)
Related papers
Bioorganic & Medicinal Chemistry Letters, 2000
ÐA series of 3-substituted-7-(alkylidene)cephaloporin sulfones were prepared and evaluated as inhibitors of representative class A and class C serine b-lactamase. Appropriate substituents resulted in a 1000-fold improvement in the inhibition of the class A enzymes and a simultaneous 20-fold improvement in the inhibition of class C. These new compounds have achieved the goal of creating broad scale inhibitors in the cephalosporin series.
Synthesis of New Cephalosporins of Expected Improved Activity and Resistance Against -Lactamases
Iraqi Journal of Pharmaceutical Sciences, 2014
The development of new cephalosporins with improved activity against resistant microbes, such as, MRSA (methicillin resistant Staph. aureus), P. aeruginosa, is of high potential. Chemical synthesis of two new series of thiadiazole linked to cysteine (series 1) and cephalosporins containing thiadiazole linked to cysteine through disulfide bond (series 2) were achieved. The chemical structures of the synthesized compounds were confirmed using spectral (FT-IR, 1H-NMR) and elemental microanalysis. The incorporation of privileged chemical moieties, such as, thiadiazole, Schiff base, cysteine and sulfonamide, has been found to have great contribution to the antimicrobial activities. Compounds of series 1 (1b-d), containing a Schiff base or a sulfonamido moiety, showed reasonable activity and were less potent than cephalexin with respect to E. coli and Staph. aureus. The new cephalosporins (series 2) showed remarkable activities on E. coli (62.5-15.6µg/ml) and staph. aureus (31.2-62.5µg/...
Asian Journal of Chemistry
INTRODUCTION The β-lactam family is the biggest and most important class of clinical antibiotics 1 . Not only the biggest, it is also the safest and the most effective broad spectrum bactericidal anti-microbial agents available to the clinician and have therefore become the most widely prescribed of all antibiotics 2 . Their sales are estimated at US$ 15 billion, so they represent the major biotechnology products with worldwide dosage sales at around 65 % of the total market of antibiotics 3 . All of these semi-synthetic antibiotics derive from the 7-aminocephalos-poranic acid composed of a β-lactam ring fused with a dihydrothiazine ring, but differ in the nature of the substituents attached at the 3-and or 7-positions of the cephem ring. These substituent affect either the pharmacokinetic properties (3-position) or the antibacterial spectrum (7-position) of the cephalosporins 4 . Currently, bacteria have shown resistance to β-lactam antibiotics by producing β-lactamases, which degr...
Computational analysis of the interactions of a novel cephalosporin derivative with β-lactamases
BMC Structural Biology
Background: One of the main concerns of the modern medicine is the frightening spread of antimicrobial resistance caused mainly by the misuse of antibiotics. The researchers worldwide are actively involved in the search for new classes of antibiotics, and for the modification of known molecules in order to face this threatening problem. We have applied a computational approach to predict the interactions between a new cephalosporin derivative containing an additional β-lactam ring with different substituents, and several serine β-lactamases representative of the different classes of this family of enzymes. Results: The results of the simulations, performed by using a covalent docking approach, has shown that this compound, although able to bind the selected β-lactamases, has a different predicted binding score for the two βlactam rings, suggesting that one of them could be more resistant to the attack of these enzymes and stay available to perform its bactericidal activity. Conclusions: The detailed analysis of the complexes obtained by these simulations suggests possible hints to modulate the affinity of this compound towards these enzymes, in order to develop new derivatives with improved features to escape to degradation.
Penicillin Sulfone Inhibitors of Class D -Lactamases
Antimicrobial Agents and Chemotherapy, 2010
OXA -lactamases are largely responsible for -lactam resistance in Acinetobacter spp. and Pseudomonas aeruginosa, two of the most difficult-to-treat nosocomial pathogens. In general, the -lactamase inhibitors used in clinical practice (clavulanic acid, sulbactam, and tazobactam) demonstrate poor activity against class D -lactamases. To overcome this challenge, we explored the abilities of -lactamase inhibitors of the C-2-and C-3-substituted penicillin and cephalosporin sulfone families against OXA-1, extended-spectrum OXA-10, OXA-14, and OXA-17), and carbapenemase-type (OXA-24/40) class D -lactamases. Three C-2-substituted penicillin sulfone compounds (JDB/LN-1-255, JDB/LN-III-26, and JDB/ASR-II-292) showed low K i values for the OXA-1 -lactamase (0.70 ؎ 0.14 3 1.60 ؎ 0.30 M) and demonstrated significant K i improvements compared to the C-3-substituted cephalosporin sulfone (JDB/DVR-II-214), tazobactam, and clavulanic acid. The C-2-substituted penicillin sulfones JDB/ASR-II-292 and JDB/LN-1-255 also demonstrated low K i s for the OXA-10, -14, -17, and -24/40 -lactamases (0.20 ؎ 0.04 3 17 ؎ 4 M). Furthermore, JDB/LN-1-255 displayed stoichiometric inactivation of OXA-1 (the turnover number, i.
Penicillin Sulfone Inhibitors of Class D β-Lactamases
Antimicrobial Agents and Chemotherapy, 2010
ABSTRACTOXA β-lactamases are largely responsible for β-lactam resistance inAcinetobacterspp. andPseudomonas aeruginosa, two of the most difficult-to-treat nosocomial pathogens. In general, the β-lactamase inhibitors used in clinical practice (clavulanic acid, sulbactam, and tazobactam) demonstrate poor activity against class D β-lactamases. To overcome this challenge, we explored the abilities of β-lactamase inhibitors of the C-2- and C-3-substituted penicillin and cephalosporin sulfone families against OXA-1, extended-spectrum (OXA-10, OXA-14, and OXA-17), and carbapenemase-type (OXA-24/40) class D β-lactamases. Three C-2-substituted penicillin sulfone compounds (JDB/LN-1-255, JDB/LN-III-26, and JDB/ASR-II-292) showed lowKivalues for the OXA-1 β-lactamase (0.70 ± 0.14 → 1.60 ± 0.30 μM) and demonstrated significantKiimprovements compared to the C-3-substituted cephalosporin sulfone (JDB/DVR-II-214), tazobactam, and clavulanic acid. The C-2-substituted penicillin sulfones JDB/ASR-II-...
Journal of Pharmacy and Pharmacology 4 (2016) 212-225, 2016
An approach of using molinspiration calculations and molecular docking on PBPs (penicillin-binding proteins) and certain β-lactamases is employed to predict the molecular properties, bioactivity and resistance of newer and reference cephalosporins. The previously synthesized cephalosporins 1-8 and reference cephalosporins were subjected to extensive evaluations by calculating the molecular properties, drug-likeness scores on the bases of Lipinski's rule and bioactivity prediction using the method of molinspiration web-based software. The TPSA (topological polar surface area), OH-NH interactions, n-violation and the molinspiration Log partition coefficient (miLogP) values were also calculated. The investigated cephalosporins were subjected to molecular docking study on PBPs (1pyy) and on β-lactamases produced by S. aureus, K. pneumonia, E. coli and P. auroginosa using 1-click-docking website. Molecular properties of 1-8 recorded higher TPSA than cephalexin and were lower than the reference cephalosporins and do not fulfill the requirements for Lipinski's rule. Bioactivities of 1-8 were predicted to be less and their docking scores on PBPs were comparable to those of the reference cephalosporins, particularly ceftobiprole. The references recorded various docking scores on the above β-lactamases and as expected, ceftobiprole recorded the lowest scores on all β-lactamases. Cephalosporins 1-8 recorded various docking scores on β-lactamases. Molecular docking studies on PBPs and β-lactamases are considered as very useful, reliable and practical approach for predicting the bioactivity scores and to afford some information about the stability and selectivity of the newly proposed cephalosporins against β-lactamases of certain pathogenic microbes, such as P. auroginosa and MRSA, by recording the relative docking scores in comparison with those of reference cephalosporins.
Current Challenges in Antimicrobial Chemotherapy: Focus on β-Lactamase Inhibition
Drugs, 2010
The use of the three classical b-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam) in combination with b-lactam antibacterials is currently the most successful strategy to combat b-lactamase-mediated resistance. However, these inhibitors are efficient in inactivating only class A b-lactamases and the efficiency of the inhibitor/antibacterial combination can be compromised by several mechanisms, such as the production of naturally resistant class B or class D enzymes, the hyperproduction of AmpC or even the production of evolved inhibitor-resistant class A enzymes. Thus, there is an urgent need for the development of novel inhibitors. For serine active enzymes (classes A, C and D), derivatives of the b-lactam ring such as 6-b-halogenopenicillanates, b-lactam sulfones, penems and oxapenems, monobactams or trinems seem to be potential starting points to design efficient molecules (such as AM-112 and LK-157). Moreover, a promising nonb-lactam molecule, NXL-104, is now under clinical development. In contrast, an ideal inhibitor of metallo-b-lactamases (class B) remains to be found, despite the huge number of potential molecules already described (biphenyl tetrazoles, cysteinyl peptides, mercaptocarboxylates, succinic acid derivatives, etc.). The search for such an inhibitor is complicated by the absence of a covalent intermediate in their catalytic mechanisms and the fact that b-lactam derivatives often behave as substrates rather than as inhibitors. Currently, the most promising broad-spectrum inhibitors of class B enzymes are molecules presenting chelating groups (thiols, carboxylates, etc.) combined with an aromatic group.