Copper mediated one-pot synthesis of quinazolinones and exploration of piperazine linked quinazoline derivatives as anti-mycobacterial agents

A facile method was developed for the synthesis of quinazolinone derivatives in a one-pot condensation reaction via in situ amine generation using ammonia as the amine source and with the formation of four new C–N bonds in good to excellent yields. With the optimised method, we synthesized a library of piperazine linked quinazoline derivatives and the synthesized compounds were evaluated for their inhibitory activity against Mycobacterium tuberculosis. The compounds 8b, 8e, 8f, 8m, 8n and 8v showed potent anti-mycobacterial activity with MIC values of 2–16 μg mL⁻¹. All the synthesized compounds follow Lipinski''s rules for drug likeness.

A facile method was developed for the synthesis of quinazolinone derivatives in a one-pot condensation reaction via in situ amine generation using ammonia as the amine source and with the formation of four new C–N bonds in good to excellent yields.     

Hepatoprotective Bile Acid Co-Drug of Isoniazid: Synthesis,Kinetics and Investigation of Antimycobacterial Potential

Pharmaceutical Chemistry Journal - The long-course treatment of tuberculosis with isoniazid (INH) leads to hazardous side effects on liver and poor patient compliance. To overcome these toxic...     

Anesthetic management of premature conjoined twins posted for nonseparation emergency surgery

Craniopagus conjoined twins are rare, and the chance that an anesthesiologist might face the challenge of providing anesthesia for this condition is very rare. The incidence of conjoined twins ranges from 1 : 50 000 to 1 : 200 000 births. We describe the anesthetic management of a pair of premature craniopagus conjoined twins posted for emergency surgery prior to their separation.     

Transient bacteraemia: a possible cause of sudden life threatening events

The concept proposed is that transient bacteraemia occurring in otherwise healthy individuals can cause acute life threatening events due to bacterial toxaemia even though the bacteraemia is rapidly cleared (<20 min). This is most likely to occur in infancy at around two to three months of age when anti-toxin IgG reaches its nadir. Sudden unexpected death in infancy, acute life threatening events, haemorrhagic shock and encephalopathy, and the triad of retinal haemorrhage, encephalopathy and bilateral thin film subdural haematomata are conditions which could be caused by this mechanism. Investigations need to be directed to measuring bacterial toxins in blood, CSF and urine; anti-toxin IgG in blood; and bacterial specific nucleic acid sequences in blood, CSF and urine using polymerase chain reaction in order to confirm recent bacteraemia. Furthermore the upper respiratory tract bacterial flora should be mapped in cases and appropriately matched live healthy community controls. Sudden onset, profound life threatening physiological dysfunction occurring in later life could also be caused by a similar mechanism and should be investigated in a similar way; candidate conditions include epilepsy, migraine, stroke and cardiac arrhythmias.     

Nuclear gyrB encodes a functional subunit of the Plasmodium falciparum gyrase that is involved in apicoplast DNA replication

The DNA replication machinery of the Plasmodium falciparum apicoplast is a validated drug target. Nuclear-encoded gyrase subunits are predicted to play a critical role in maintaining DNA topology during the D-loop/bi-directional ori replication process of the parasite. We show the presence of P. falciparum gyrase subunits in parasite lysates by using antibodies generated against recombinant gyrase A and B. The ATPase activity of PfGyrB was inhibited by novobiocin that also caused parasite death in culture. Reduction of apicoplast/nuclear DNA ratio in the presence of novobiocin indicated that the drug targets apicoplast DNA replication. Molecular modeling of gyrase A and B subunits revealed extensive fold conservation with the Escherichia coli counterparts as well as the presence of a long disordered loop adjacent to the ATPase domain of PfGyrB. Our results have implications for development of PfGyrB as a drug target against malaria.     

Porin of Shigella dysenteriae activates mouse peritoneal macrophage through Toll-like receptors 2 and 6 to induce polarized type I response

Porin of Shigella dysenteriae type 1 coexpressed Toll-like receptor (TLR) 2 and TLR6 on peritoneal cavity (PerC) macrophages (MPhi) of C57BL/6 mice implicating that both the TLRs are essential as a combinatorial repertoire to recognize the protein. Besides TLRs, mRNA for MyD88 and TRAF6, and nuclear translocation of NF-kappaB were enhanced that indicate their involvement in tandem in the activity of porin. The protein selectively up-regulated CD80 on the activated MPhi together with MHC class II molecule and CD40, and had no effect on CD86 expression. The porin-induced profile of MIP-1alpha, MIP-1beta and RANTES showed strong bias for chemokines correlated with M1 polarization. Intracellular expression and release of TNF-alpha and IL-12 in presence of porin was found to be TLR2 and NF-kappaB dependent. Induction of TNF-alpha and IL-12 along with the chemokine profile suggests type I polarization of the MPhi that would influence Th1-type response.     

A class of Covariate-Adjusted Response-Adaptive Allocation Designs for Multitreatment Binary Response Trials

A class of covariate-adjusted response-adaptive randomization procedures is developed for binary treatment outcomes in a phase III clinical trial set up involving multiple treatments. The target allocation is developed by combining the ethical aspects with statistical precision under the existence of treatment covariate interaction. Relevant measures of the performance for the proposed allocation designs are studied and compared.     

Molecular mechanisms of resistance to antibiotics in Bartonella bacilliformis

OBJECTIVES: Bartonella bacilliformis is the aetiological agent of Carrion's disease. Although ciprofloxacin, rifampicin and erythromycin have been successfully used in the treatment of the disease, failures and relapses have been reported. The objective of our study was to select in vitro mutants resistant to antibiotics in order to determine the frequency of mutations and to characterize the mechanism of resistance at the molecular level. METHODS: Antibiotic-resistant mutants were selected by serial passages of bacteria on blood agar plates containing antibiotics. Candidate genes involved in resistance were amplified and sequenced and compared in order to look at mutations associated with antibiotic resistance. RESULTS: Ciprofloxacin-, rifampicin- and erythromycin-resistant mutants were obtained after five, three and four passages, respectively. Conversely, no mutant was obtained with either gentamicin or doxycycline even after 16 passages. The ciprofloxacin mutant contained an amino acid change at position 87 (Asp --> Asn) in its quinolone resistance-determining region of the DNA gyrase protein, whereas the rifampicin-resistant strain had an amino acid change at position 531 (Ser --> Phe) in the rifampicin resistance-determining region of the rpoB gene. Similarly, the erythromycin-resistant mutant showed an A2058G mutation in the 23S rRNA gene. CONCLUSIONS: According with the current knowledge on the treatment of human bartonellosis, we believe that doxycycline in association with gentamicin may be the preferred regimen for the treatment of the acute and eruptive stages of Carrion's disease, but clinical trials are warranted to support our findings.     

Detection of HSV-1 variants highly resistant to the helicase-primase inhibitor BAY 57-1293 at high frequency in 2 of 10 recent clinical isolates of HSV-1

OBJECTIVES: BAY 57-1293 is a helicase-primase inhibitor (HPI) from a new class of antivirals that are highly efficacious in herpes simplex virus (HSV)-1 animal infection models. Resistant mutants with point mutations in the helicase (UL5) were reported to be present in laboratory isolates at a low frequency of approximately 10(-6). In contrast, we have shown elsewhere that some laboratory isolates contain resistant variants at higher frequency (10(-4)). Therefore, we screened 10 recent clinical isolates of HSV-1 for BAY 57-1293-resistant virions. METHODS: Clinical isolates were screened by a plaque reduction assay in Vero cells to determine the frequency of occurrence of BAY 57-1293-resistant variants. The helicase gene for the resistant variants was sequenced. RESULTS: One isolate contained highly resistant variants at 10(-4) and another at 10(-5). Both variants contained a previously reported BAY 57-1293 resistance mutation (K356N) in UL5 and were >5000-fold resistant. CONCLUSIONS: Occurrence of HPI-resistant viruses at high frequency in a clinical isolate is intriguing. Two alternative hypotheses are proposed to explain this phenomenon. It is also surprising that two unrelated clinical isolates contain an identical HPI resistance mutation. These results have important implications for HPI drug-resistance monitoring during subsequent clinical trials.