Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections.Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AzD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity.The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase(GyrB,IC_(50)=49 nmol/L)and a modest inhibitory effect on TopoⅣ(ParE,IC_(50)=1.513μmol/L)of Staphylococcus aureus.It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration(MIC)of less than 0.03μg/mL,which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S.aureus.Compound 28 had better protective effects than the positive control drugs such as DS-2969(5)and AZD5099(6)in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus(MRSA)infection.It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models.Moreover,compound 28 has much lower mitochondrial toxicity than AZD5099(6)as well as excellent therapeutic indexes and pharmacokinetic properties.At present,compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection.On the other hand,compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli(MIC=1μg/mL),which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently.In addition,the structure-activity relationships of the compounds were also studied.

Determination of deferasirox particle size distribution via laser diffraction and its application in establishing a correlation between particle size and drug dissolution in vitro

Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle size of its active pharmaceutical ingredient(API) should be strictly controlled during the manufacturing process. In the present study, laser diffraction was adopted to measure the particle size distribution of deferasirox API. We also developed and validated an accurate and convenient method by investigating important optical parameters and sample dispersing conditions. The relative standard deviation values, namely, d(0.1), d(0.5), d(0.9), and d(4,3), measured via methodology validation and actual sample measurement were < 3%. The dissolution curves of several batches of dispersible tablets prepared using deferasirox with different particle sizes were compared in the four dissolved media to investigate the influence of particle size on drug dissolution in vitro. Results indicated that the particle size distribution of deferasirox API significantly affected the release of its dispersible tablet.

The synthesis and antibacterial activity evaluation of oxazolidinone-deferasirox conjugates

We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the“Trojan horse”strategy.The conjugates could combine with Fe^(3+)ions as the deferasirox.However,both conjugates were inactive against tested bacteria,including S.aureus,E.coli,A.baumannii,and P.aeruginosa.The results suggested that the synthesized iron chelator deferasirox was not suitable as a siderophore of the bacteria to transport the antibiotic,or the coupling linker of the synthesized conjugates could not be hydrolyzed to release the oxazolidinone in the cytoplasm.Therefore,the design and synthesis of oxazolidinone-deferasirox conjugates need further exploration.