A convenient one-pot synthesis of N-substituted amidoximes and their application toward 1,2,4-oxadiazol-5-ones

The first direct one-pot approach for the synthesis of N-substituted amidoximes from secondary amides or the intermediate amides has been developed. Through the Ph₃P–I₂-mediated dehydrative condensation, a variety of N-aryl and N-alkyl amidoximes (R¹(C NOH)NHR², where R¹ or R² = aryl, alkyl, or benzyl) were readily afforded under mild conditions and short reaction times. The synthetic application of the obtained amidoximes has also been demonstrated through the formation of 1,2,4-oxadiazolones via base-mediated carbonylative cyclization with 1,1′-carbonyldiimidazole.

Ph₃P–I₂ mediated one-pot synthesis of N-substituted amidoximes via imidoyl iodide was developed. The synthesis of 1,2,4-oxadiazol-5-ones was also demonstrated.     

Mycotic aneurysm caused by Burkholderia pseudomallei with negative blood cultures

We describe a case of bacterial aortitis caused by Burkholderia pseudomallei. This patient presented with prolonged fever and hoarseness of voice. Aneurysm removal with Dacron graft replacement was performed, followed by a prolonged course of antibiotics. The patient has progressed satisfactorily without recurrence of symptoms. Previous case reports are summarized.     

Antimicrobial resistance among Clostridium perfringens isolated from various sources in Thailand

Antimicrobial resistance among Clostnridium perfringens isolated from feces of humans and pigs, food and other environmental sources was examined by testing of 201 PCR-confirmed strains for resistance to 7 antimicrobial agents. The minimal inhibitory concentrations (MICs) were determined by the agar dilution method. Overall, C. perfringens showed the highest resistance to tetracycline (56.2%), followed by imipenem (24.9%), metronidazole (9.5%), penicillin G (9%), vancomycin (4.5%), chloramphenicol (3%) and ceftriaxone (1%). The majority of the isolated strains from pig feces (77.8%), environment (72.7%), human feces (44.9%) and food (28%) showed resistance to tetracycline. Strains isolated from human feces only showed low resistance to ceftriaxone (2.5%) and vancomycin (10.1%). Penicillin G had high activity, with overall MIC50 and MIC90 of 0.06 and 1.0 microg/ml, respectively, and low rate of resistance (10-12% for strains isolated from humans, animals and food). Among 62.7% of antimicrobial resistant strains, 39.3% were resistant to a single drug and 23.4% were multiple-drug resistant (MDR). Of overall 47 MDR strains, 63.8% were derived from human feces and were resistant to two to six drugs.     

Ex Vivo Activity of Endoperoxide Antimalarials,Including Artemisone and Arterolane,against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

Novel synthetic endoperoxides are being evaluated as new components of artemisinin combination therapies (ACTs) to treat artemisinin-resistant Plasmodium falciparum malaria. We conducted blinded ex vivo activity testing of fully synthetic (OZ78 and OZ277) and semisynthetic (artemisone, artemiside, artesunate, and dihydroartemisinin) endoperoxides in the histidine-rich protein 2 enzyme-linked immunosorbent assay against 200 P. falciparum isolates from areas of artemisinin-resistant malaria in western and northern Cambodia in 2009 and 2010. The order of potency and geometric mean (GM) 50% inhibitory concentrations (IC₅₀s) were as follows: artemisone (2.40 nM) > artesunate (8.49 nM) > dihydroartemisinin (11.26 nM) > artemiside (15.28 nM) > OZ277 (31.25 nM) > OZ78 (755.27 nM). Ex vivo activities of test endoperoxides positively correlated with dihydroartemisinin and artesunate. The isolates were over 2-fold less susceptible to dihydroartemisinin than the artemisinin-sensitive P. falciparum W2 clone and showed sensitivity comparable to those with test endoperoxides and artesunate, with isolate/W2 IC₅₀ susceptibility ratios of <2.0. All isolates had P. falciparum chloroquine resistance transporter mutations, with negative correlations in sensitivity to endoperoxides and chloroquine. The activities of endoperoxides (artesunate, dihydroartemisinin, OZ277, and artemisone) significantly correlated with that of the ACT partner drug, mefloquine. Isolates had mutations associated with clinical resistance to mefloquine, with 35% prevalence of P. falciparum multidrug resistance gene 1 (pfmdr1) amplification and 84.5% occurrence of the pfmdr1 Y184F mutation. GM IC₅₀s for mefloquine, lumefantrine, and endoperoxides (artesunate, dihydroartemisinin, OZ277, OZ78, and artemisone) correlated with pfmdr1 copy number. Given that current ACTs are failing potentially from reduced sensitivity to artemisinins and partner drugs, newly identified mutations associated with artemisinin resistance reported in the literature and pfmdr1 mutations should be examined for their combined contributions to emerging ACT resistance.