Recent developments in chemical reactivity of N,N-dimethylenamino ketones as synthons for various heterocycles

The current review presents recent progress in the utility of N,N-dimethyl enaminones as building blocks for a diverse range of acyclic, carbocyclic, five- and six-membered heterocyclic a broad range of heterocyclic and fused heterocyclic derivatives. Most importantly, these N,N-dimethyl analogues have proven to be of biological interest and provide an access to new class of biologically active heterocyclic compounds for biomedical applications. All of these topics are drawn from the recent literature till 2016

1,3,4-Thiadiazole and 1,2,4-triazole-3(4 H )-thione bearing salicylate moiety: synthesis and evaluation as anti- Candida albicans

Dramatically increased occurrence of both superficial and invasive fungal infections has been observed. Candida albicans appear to be the main etiological agent of invasive fungal infections. The anti-C. albicans activity of thiosemicarbazide, 1,3,4-Thiadiazole, and 1,2,4-triazole-3(4H)-thione compounds (compounds 3-23) were investigated. The MIC values of thiadiazole and triazole derivatives 10-23 were in the range of 0.08-0.17 µmol mL-1, while that of fluconazole was 0.052 µmol mL-1. Compound 11 (5-(2-(4-chlorobenzyloxy)phenyl)-N-allyl-1,3,4-thiadiazol-2-amine) and compound 18 (5-(2-(4-chlorobenzyloxy)phenyl)-4-allyl-2H-1,2,4-triazole-3(4H)-thione) were found to be the most active compounds, with MIC values of 0.08 µmol mL-1. The newly synthesized thiadiazole and triazole compounds (compounds 10-23) showed promising anti-Candida activity. The allyl substituent-bearing compounds 11 and 18 exhibited significant anti-Candida albicans activity and showed a binding mode as well as the fluconazole x-ray structure

Design, synthesis and molecular modeling study of substituted indoline-2- ones and spiro[indole-heterocycles] with potential activity against Gram-positive bacteria

Longstanding and firsthand infectious diseases are challenging community health threats. A new series of isatin derivatives bearing β-hydroxy ketone, chalcone, or spiro-heterocycle moiety, was synthesized in a good yield. Chemical structures of the synthesized compounds were elucidated using spectroscopic techniques and elemental analysis. Antibacterial activities of the compounds were then evaluated in vitro and by in silico modeling. The compounds were more active against Gram-positive bacteria, Staphylococcus aureus (MIC = 0.026–0.226 mmol L–1) and Bacillus subtilis (MIC = 0.348–1.723 mmol L–1) than against Gram-negative bacteria (MIC = 0.817–7.393 mmol L–1). Only 3-hydroxy-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethyl)indolin-2-one (1b) was found as active as imipenem against S. aureus (MIC = 0.026 mmol L–1). In silico docking of the compounds in the binding sites of a homology modeled structure of S. aureus histidine kinase-Walk allowed us to shed light on the binding mode of these novel inhibitors. The highest antibacterial activity of 1b is consistent with its highest docking score values against S. aureus histidine kinase

Enhancement of ciprofloxacin activity by incorporating it in solid lipid nanoparticles

Purpose: To incorporate ciprofloxacin (CIP) into solid lipid nanoparticles (SLN) in order to enhance its biopharmaceutical properties and antibacterial activity.Methods: A sonication melt-emulsification method was employed for the preparation of CIP-loaded SLN. The composition of the SLN was varied in order to investigate factors such as lipid type and combination ratio, drug to lipid ratio, and surfactant ratio. The produced SLN formulations wereevaluated for their particle size and shape, zeta potential, and entrapment efficiency. In addition, the effect of SLN formulation composition on its drug release profile and antimicrobial activity against Escherichia coli, Pseudomonas Aeruginosa, and Staphylococcus Aureus was also investigated.Results: The generated nanoparticles had particle size in the range of 165 to 320 nm. The zetapotential values were generally low within ± 5. All formulations exhibited entrapment efficiency between 50 and 90 %. CIP release exhibited a biphasic release profile with a low burst phase, followed by uniform controlled-release behavior of various rates. SLN-loaded CIP exhibited one-fold reduction in minimum inhibitory concentration (MIC) and caused significant inhibition of all the three bacterial strains tested, when compared with pure CIP.Conclusion: Loading of CIP into SLN significantly enhances its antimicrobial activity in vitro which can translate to significant enhancement of therapeutic outcomes by minimizing the dose-dependent adverse and side effects and/or enhancing the antimicrobial spectrum of activity. Keywords: Solid lipid nanoparticles, Sonication melt-emulsification, Ciprofloxacin, Escherichia coli, Pseudomonas aeruginos

Synthesis, characterization, antimicrobial activity and molecular docking studies of combined pyrazol-barbituric acid pharmacophores

Purpose: To synthesize, and determine the antibacterial activity and binding mode of new pyrazolbarbituric acid derivatives in a search for new antimicrobial agents.Methods: One-pot multi-component reaction of aldehyde derivatives, barbituric acid and 3-methyl-1- phenyl-1H-pyrazol-5(4H)-one in the presence of NHEt2 to afford Michael adduct was carried out. The reaction was carried out in water and afforded new heterocycles in a one-step fashion, with expedient work-up and high yield without extraction and purification steps. The synthesized compounds were evaluated for antimicrobial activity using agar disc diffusion. Molecular docking approach via MOE-Dock program was applied to predict the binding interactions of some of the new pyrazol-barbituric acid derivatives against six different target proteins downloaded from Protein Data Bank.Results: A series of pyrazole-barbituric acid derivatives were successfully synthesized and characterized. The synthesized compounds showed moderate to very good antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC29212, as well as also antifungal activity against Candida albicans ATCC 10400Conclusion: A series of pyrazole-barbituric acid derivatives has been synthesized and some of them display antimicrobial activities.Keywords: Pyrazole, Barbituric acid, Pyrazole-barbituric acid derivatives, Antimicrobial activity, Molecular dockin

Activity of ceftolozane/tazobactam against surveillance and ‘problem’ Enterobacteriaceae, Pseudomonas aeruginosa and non-fermenters from the British Isles

Background: We assessed the activity of ceftolozane/tazobactam against consecutive isolates collected in the BSAC Bacteraemia Surveillance from 2011 to 2015 and against ‘problem’ isolates sent to the UK national reference laboratory from July 2015, when routine testing began. Methods: Susceptibility testing was by BSAC agar dilution with resistance mechanisms identified by PCR and interpretive reading. Results: Data were reviewed for 6080 BSAC surveillance isolates and 5473 referred organisms. Ceftolozane/tazobactam had good activity against unselected ESBL producers in the BSAC series, but activity was reduced against ertapenem-resistant ESBL producers, which were numerous among reference submissions. AmpC-derepressed Enterobacter spp. were widely resistant, but Escherichia coli with raised chromosomal AmpC frequently remained susceptible, as did Klebsiella pneumoniae with acquired DHA-1-type AmpC. Carbapenemase-producing Enterobacteriaceae were mostly resistant, except for ceftazidime-susceptible isolates with OXA-48-like enzymes. Ceftolozane/tazobactam was active against 99.8% of the BSAC Pseudomonas aeruginosa isolates; against referred P. aeruginosa it was active against 99.7% with moderately raised efflux, 94.7% with strongly raised efflux and 96.6% with derepressed AmpC. Resistance in P. aeruginosa was largely confined to isolates with metallo-β-lactamases (MBLs) or ESBLs. MICs for referred Burkholderia spp. and Stenotrophomonas maltophilia were 2–4-fold lower than those of ceftazidime. Conclusions: Ceftolozane/tazobactam is active against ESBL-producing Enterobacteriaceae; gains against other problem Enterobacteriaceae groups were limited. Against P. aeruginosa it overcame the two most prevalent mechanisms (up-regulated efflux and derepressed AmpC) and was active against 51.9% of isolates non-susceptible to all other β-lactams, rising to 80.9% if ESBL and MBL producers were excluded

Cooccurrence of NDM-1, ESBL, RmtC, AAC(6′)-Ib, and QnrB in Clonally Related Klebsiella pneumoniae Isolates Together with Coexistence of CMY-4 and AAC(6′)-Ib in Enterobacter cloacae Isolates from Saudi Arabia

The aim of this study was to investigate the mechanisms responsible for resistance to antimicrobials in a collection of enterobacterial isolates recovered from two hospitals in Saudi Arabia. A total of six strains isolated from different patients showing high resistance to carbapenems was recovered in 2015 from two different hospitals, with four being Klebsiella pneumoniae and two Enterobacter cloacae. All isolates except one K. pneumoniae were resistant to tigecycline, but only one K. pneumoniae was resistant to colistin. All produced a carbapenemase according to the Carba NP test, and all were positive for the EDTA-disk synergy test for detection of MBL. Using PCR followed by sequencing, the four K. pneumoniae isolates produced the carbapenemase NDM-1, while the two E. cloacae isolates produced the carbapenemase VIM-1. Genotyping analysis by Multilocus Sequence Typing (MLST) showed that three out of the four K. pneumoniae isolates were clonally related. They had been recovered from the same hospital and belonged to Sequence Type (ST) ST152. In contrast, the fourth K. pneumoniae isolate belonged to ST572. Noticeably, the NDM-1-producing K. pneumoniae additionally produced an extended-spectrum ß- lactamase (ESBL) of the CTX-M type, together with OXA-1 and TEM-1. Surprisingly, the three clonally related isolates produced different CTX-M variants, namely, CTX-M- 3, CTX-M-57, and CTX-M-82, and coproduced QnrB, which confers quinolone resistance, and the 16S rRNA methylase RmtC, which confers high resistance to all aminoglycosides. The AAC(6′)-Ib acetyltransferase was detected in both K. pneumoniae and E. cloacae. Mating-out assays using Escherichia coli as recipient were successful for all isolates. The Bla NDM-1 gene was always identified on a 70- kb plasmid, whereas the Bla VIM-1 gene was located on either a 60-kb or a 150-kb plasmid the two E. cloacae isolates, respectively. To the best of our knowledge, this is the first report of the coexistence of an MBL (NDM-1), an ESBL (CTX-M), a 16S rRNA methylase (RmtC), an acetyltransferase (AAC[6′]-Ib), and a quinolone resistance enzyme (QnrB) in K. pneumoniae isolates recovered from different patients during an outbreak in a Saudi Arabian hospital

Molecular characteristics of extended-spectrum β-lactamase-producing Escherichia coli in Riyadh: emergence of CTX-M-15-producing E. coli ST131

BACKGROUND: The prevalence of extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) has increased recently. The aim of this study was to further characterise and to assess the occurrence of ESBL-EC in Riyadh, to use pulsed field gel electrophoresis (PFGE) typing to investigate the epidemiology of ESBL-EC and to determine the prevalence of ST131 in ESBL-EC. METHODS: A total of 152 E. coli isolates were collected at a tertiary hospital in Riyadh from September 2010 to June 2011. Genotypic and phenotypic methods were used to characterise ESBLs. PFGE was used to determine genetic relatedness. Detection of ST131 and CTX-M-like ESBLs was performed using real-time PCR. RESULTS: Of 152 strains, 31 were positive for ESBLs by phenotypic methods. The bla(CTX-M-15) gene was highly prevalent (30/31 strains, 96.77%) among the 31 ESBL-positive E. coli strains. The bla(CTX-M-27) gene was detected in one strain. Twenty (64.5%) out of 31 of ESBL-EC were ST131. PFGE revealed 29 different pulsotypes. CONCLUSIONS: Our study documented the high prevalence of ESBLs in E. coli isolates, with CTX-M-15 as the predominant ESBL gene. ST131 clone producing CTX-M-15 has a major presence in our hospital. The high prevalence of CTX-M producers was not due to the spread of a single clone. To the best of our knowledge, this study represents the first report of CTX-M-15 and CTX-M-27 β-lactamases and the detection of the ST131 clone in Saudi E. coli isolates

A Spotlight on the Egyptian Honeybee (Apis mellifera lamarckii)

Egypt has an ongoing long history with beekeeping, which started with the ancient Egyptians making various reliefs and inscriptions of beekeeping on their tombs and temples. The Egyptian honeybee (Apis mellifera lamarckii) is an authentic Egyptian honeybee subspecies utilized in apiculture. A. m. lamarckii is a distinct honeybee subspecies that has a particular body color, size, and high levels of hygienic behavior. Additionally, it has distinctive characteristics; including the presenceof the half-queens, an excessive number of swarm cells, high adaptability to climatic conditions, good resistance to specific bee diseases, including the Varro disorder, and continuous breeding during the whole year despite low productivity, using very little propolis, and tending to abscond readily. This review discusses the history of beekeeping in Egypt and its current situation in addition to its morphology, genetic analysis, and distinctive characters, and the defensive behaviors of native A. m.lamarckii subspecies.publishersversionPeer reviewe