Synthesis and biological properties of a new series of anti-MRSA β-lactams; 2-(thiazol-2-ylthio)carbapenems

Shinagawa, Hisatoshi; Yamaga, Hiroshi; Houchigai, Hitoshi; Sumita, Yoshihiro; Sunagawa, Makoto

doi:10.1016/s0968-0896(96)00273-8

Cited by 31 publications

(13 citation statements)

References 40 publications

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“…T he chemistry of aminothiazoles and their derivatives has attracted the attention of chemists, because they exhibit important biological activity in medicinal chemistry [1], such as antibiotic, anti-inflammatory, antihelmintic, or fungicidal properties [2][3][4]. 2-Aminothiazoles are known mainly as biologically active compounds with a broad range of activities and as intermediates in the synthesis of antibiotics, well-known sulfa drugs, and some dyes [5,6].…”

Section: Introductionmentioning

confidence: 99%

Experimental and theoretical investigation of the molecular and electronic structure of N′‐benzylidene‐N‐[4‐(3‐methyl‐3‐phenyl‐cyclobutyl)‐thiazol‐2‐yl]‐chloro‐acetic acid hydrazide

Demir

Di̇nçer

Çukurovalı

et al. 2011

Int J of Quantum Chemistry

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The title compound, N 0 -benzylidene-N-[4-(3-methyl-3-phenylcyclobutyl)-thiazol-2-yl]-chloro-acetic acid hydrazide, has been synthesized and characterized by elemental analysis, IR, 1 H and 13 C NMR, and X-ray single crystal diffraction. The compound crystallizes in the orthorhombic space group P 21 21 21 with a ¼ 5.8671 (3) Å , b ¼ 17.7182 (9) Å , and c ¼ 20.6373 (8) Å . Moreover, the molecular geometry from X-ray experiment, the molecular geometry, vibrational frequencies, and gauge-including atomic orbital 1 H and 13 C chemical shift values of the title compound in the ground state have been calculated by using the Hartree-Fock and density functional methods (B3LYP) with 6-31G(d) and 6-31G(d,p) basis sets. The results of the optimized molecular structure are exhibited and compared with the experimental X-ray diffraction. Besides, molecular electrostatic potential, Frontier molecular orbitals, and thermodynamic properties of the title compound were determined at B3LYP/6-31G(d) levels of theory.

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Section: Introductionmentioning

confidence: 99%

Experimental and theoretical investigation of the molecular and electronic structure of N′‐benzylidene‐N‐[4‐(3‐methyl‐3‐phenyl‐cyclobutyl)‐thiazol‐2‐yl]‐chloro‐acetic acid hydrazide

Demir

Di̇nçer

Çukurovalı

et al. 2011

Int J of Quantum Chemistry

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“…We previously reported that a 2-(4-arylthiazol-2-ylthio)-1␤-methylcarbapenem, SM-17466, and its derivatives exhibited potent activity against methicillin-resistant Staphylococcus aureus (MRSA) corresponding to a high affinity for bacterial penicillin-binding protein 2a (PBP2a) (22,28). SM-17466 showed a higher level of activity against Enterococcus faecium than existing carbapenems, prompting us to search for new carbapenems with potent activity against MRSA and vancomycin-resistant E. faecium (VRE) (25).…”

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confidence: 99%

In Vitro and In Vivo Antibacterial Activities of SM-216601, a New Broad-Spectrum Parenteral Carbapenem

Ueda

Kanazawa

Eguchi

et al. 2005

Antimicrob Agents Chemother

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SM-216601 is a novel parenteral 1␤-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC 90 ) was 2 g/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC 90 ‫؍‬ 8 g/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC 90 s of less than 0.5 g/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.

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“…We previously reported that the 2-(4-arylthiazol-2-ylthio)-1␤-methylcarbapenem SM-17466 and its derivatives exhibited potent anti-MRSA activity corresponding to a high affinity for PBP2a (23,25). Although SM-17466 showed good efficacy in a murine systemic infection model of MRSA and acceptable toxicological profiles in preliminary animal experiments, it did not show sufficient activity against E. faecium, prompting us to search for new carbapenems with potent activity against both MRSA and E. faecium, including VRE.…”

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confidence: 99%

In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria

Ueda

Sunagawa

2003

Antimicrob Agents Chemother

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SM-197436, SM-232721, and SM-232724 are new 1␤-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC 90 of <4 g/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamidetreated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillinintermediate and penicillin-resistant Streptococcus pneumoniae strains, ranged from <0.063 to 0.5 g/ml. These drugs were the most active ␤-lactams tested against Enterococcus faecium, and the MIC 90 s for ampicillinresistant E. faecium ranged between 8 and 16 g/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the E. faecium strain: its efficacy was superior to that of linezolid, although the MICs (2 g/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.

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Synthesis and biological properties of a new series of anti-MRSA β-lactams; 2-(thiazol-2-ylthio)carbapenems

Cited by 31 publications

References 40 publications

Experimental and theoretical investigation of the molecular and electronic structure of N′‐benzylidene‐N‐[4‐(3‐methyl‐3‐phenyl‐cyclobutyl)‐thiazol‐2‐yl]‐chloro‐acetic acid hydrazide

Experimental and theoretical investigation of the molecular and electronic structure of N′‐benzylidene‐N‐[4‐(3‐methyl‐3‐phenyl‐cyclobutyl)‐thiazol‐2‐yl]‐chloro‐acetic acid hydrazide

In Vitro and In Vivo Antibacterial Activities of SM-216601, a New Broad-Spectrum Parenteral Carbapenem

In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria

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