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novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity.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, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 µmol/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 0.03 µg/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 = 1 µg/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.

Discovery of isatin-ß-methyldithiocarbazate derivatives as New Delhi metallo- ß-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates.

New Delhi metallo-ß-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all ß-lactam antibiotics, leaving limited treatment options for NDM-1 positive pathogens. Regrettably, there are presently no effective NDM-1 inhibitors in clinical use. This compels us to seek new compounds to combat multi-drug resistant bacterial infections (MDR). In our study, Zndm19 was identified as a new NDM-1 inhibitor through virtual screening and an NDM-1 enzyme activity inhibition assay. Subsequently, we employed the checkerboard method, time-killing assay, and combined disk test to investigate the synergistic bactericidal efficacy of Zndm19 in combination with meropenem (MEM). Meanwhile, molecular docking and site-directed mutagenesis were conducted to uncover the crucial amino acid residues engaged in Zndm19 binding. Finally, we established a mice peritonitis infection model to assess the synergistic effect of Zndm19 and MEM in vivo. Our findings demonstrated that 16 µg/mL of Zndm19 inhibited NDM-1 activity without affecting NDM-1 expression, restoring the bactericidal activity of MEM against NDM-1-positive Escherichia coli in vitro. Furthermore, MET-67, ASP-124, HIS-189, and HIS-250 amino acid residues constituted the active site of Zndm19 in NDM-1. Importantly, this combination therapy exhibited synergistic anti-infection activity in the mice peritonitis infection model, leading to an approximate 60% increase in survival rates and reduction of tissue bacterial load, effectively combating bacterial infection in vivo. In summary, our research validates that the synthetic novel NDM-1 inhibitor Zndm19 holds promise as a drug to treat drug-resistant bacterial infections, especially those harboring NDM-1.

Exploration and Biological Evaluation of 1,3-Diamino-7H-pyrrol[3,2-f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors.

Dihydrofolate reductase (DHFR), a core enzyme of folate metabolism, plays a crucial role in the biosynthesis of purines and thymidylate for cell proliferation and growth in both prokaryotic and eukaryotic cells. However, the development of new DHFR inhibitors is challenging due to the limited number of scaffolds available for drug development. Hence, we designed and synthesized a new class of DHFR inhibitors with a 1,3-diamino-7H-pyrrol[3,2-f]quinazoline derivative (PQD) structure bearing condensed rings. Compound 6r exhibited therapeutic effects on mouse models of systemic infection and thigh infection caused by methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. Moreover, methyl-modified PQD compound 8a showed a strong efficacy in a murine model of breast cancer, which was better than the effects of taxol. The findings showcased in this study highlight the promising capabilities of novel DHFR inhibitors in addressing bacterial infections as well as breast cancer.

Design, synthesis and antibacterial evaluation of pleuromutilin derivatives.

We report herein the design, synthesis, and structure-activity relationship studies of pleuromutilin derivatives containing urea/thiourea functionalities. The antibacterial activities of these new pleuromutilin derivatives were evaluated in vitro against Gram-positive pathogens (GPPs) (Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium) and Mycoplasma pneumoniae by the broth dilution method. Most of the targeted compounds exhibit good potency in inhibiting the growth of pathogens including Methicillin-susceptible S. aureus (MSSA, ATCC29213, MIC: 0.0625-16 µg/mL), Methicillin-resistant S. aureus (MRSA, ATCC43300, MIC: 0.125-16 µg/mL) and M. pneumoniae (ATCC15531 MIC: 0.125-1 µg/mL, ATCC29342 MIC: 0.0625-0.25 µg/mL and drug resistant strain MIC: 0.5-2 µg/mL). In particular, the compounds 6m and 6n containing phenyl-urea group showed excellent activity with the MIC value less than 0.0625 µg/mL against S. aureus ATCC29213. The compound 6h exhibited better activity than tiamulin against Methicillin-resistant S. aureus ATCC43300.

Synthesis and anti-tumor activity evaluation of salinomycin C20-O-alkyl/benzyl oxime derivatives.

Seventeen C20-O-alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC50 values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca2+ concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20-O-alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.

A General Strategy to Synthesize ADP-7-Azido-heptose and ADP-Azido-mannoses and Their Heptosyltransferase Binding Properties.

The multistep synthesis of a novel ADP-7-azido-7-deoxy-l-glycero-ß-d-manno-heptopyranoside 2a and several analogues as heptosyltransferase ligands is described. The synthesis of the key intermediate heptoside-1-ß-phosphate 3a involved a ß-stereoselective phosphorylation of lactol 4 employing diallyl chlorophosphate as a phosphorylating reagent. Five deprotected nucleotide sugars were generated by this synthetic sequence and evaluated as heptosyltransferase substrates (KM, kcat).

A Useful Synthesis of 2-Acylamino-1,3,4-oxadiazoles from Acylthiosemicarbazides Using Potassium Iodate and the Discovery of New Antibacterial Compounds.

A useful method for the synthesis of 2-acylamino-1,3,4-oxadiazoles was developed. By using potassium iodate as an oxidant in water at 60 °C, a wide range of 2-acylamino-1,3,4-oxadiazoles were afforded in moderate to excellent yields within two hours. This method could provide a facile shortcut to generate a series of 2-acylamino-1,3,4-oxadiazoles in medicinal chemistry. Interestingly, some highly potent antibiotic compounds were found through this synthetic method, and some of them displayed a significant improvement in activity compared with the corresponding 1,4-diacylthiosemicarbazides. Compound 2n was the most active against Staphylococcus aureus with MIC (minimum inhibitory concentration) of 1.56 mg/mL, and compounds 2m and 2q were the most active against Bacillus subtilis with MIC of 0.78 mg/mL. The preliminary cytotoxic activities of the most potent compounds 2m, 2n, and 2q against the androgen-independent (PC-3) prostate cancer cell line were more than 30 µM (IC50 > 30 µM).

Cobalt(ii)-catalyzed benzylic oxidations with potassium persulfate in TFA/TFAA.

A cobalt-catalyzed C(sp3)-H oxygenation reaction to furnish aldehyde was herein reported. This transformation demonstrated high chemo-selectivity, and tolerated various methylarenes bearing electron-withdrawing substituents. This reaction provided rapid access to diverse aldehydes form methylarenes. Notably, TFA/TFAA was used for the first time as a mixed solvent in cobalt-catalyzed oxygenation of benzylic methylenes.

Multigram-scale synthesis of l,d-heptoside using a Fleming-Tamao oxidation promoted by mercuric trifluoroacetate.

An efficient multigram-scale synthesis of methyl 2,3,4,6-tetra-O-benzyl-l-glycero-α-d-manno-heptopyranoside from methyl 2,3,4-tri-O-benzyl-α-d-mannopyranoside is reported. It involves a sequence of Swern oxidation, Grignard addition and Fleming-Tamao reactions. The resulting scaffold was used as a precursor to design a small library of clickable l-heptosides. This study shows that the use of mercuric bistrifluoroacetate is required both to accelerate and to cleanly perform the Fleming-Tamao oxidation, without side-reactions.

ß-Stereoselective phosphorylations applied to the synthesis of ADP- and polyprenyl-ß-mannopyranosides.

An efficient and convenient synthetic route to glycosyl 1-ß-phosphates has been developed using diallyl chlorophosphate as a phosphorylating agent with 4-N,N-dimethylaminopyridine under mild conditions. Diallyl-glycosyl 1-ß-phosphate triesters of D-manno, L-glycero-D-manno-hepto-, D-gluco-, D-galacto-, and L-fuco-pyranose as well as lactose have been obtained by this strategy in good yields and excellent ß-selectivities. Furthermore, the diallyl 6-azido-mannosyl 1-ß-phosphate 2 was deprotected under mild conditions and converted into potentially clickable analogues of ß-mannosyl phosphoisoprenoids I and ADP-heptose II.

Vulgarisin A, a new diterpenoid with a rare 5/6/4/5 ring skeleton from the Chinese medicinal plant Prunella vulgaris.

Vulgarisin A (1), a new diterpenoid with an unprecedented 5/6/4/5 fused tetracyclic ring skeleton, has been isolated from the medicinal plant Prunella vulgaris Linn. Its structure was characterized by extensive spectroscopic methods, and the absolute configuration was secured by single crystal X-ray diffraction analysis. Compound 1 showed weak cytotoxicity against human lung carcinoma A549 cells with an IC50 value of 57.0 µM.

A novel base-induced isomerization gives access to unprecedented (E)-exo-glycals.

Bump the base: This study reports the discovery of the base-induced Z-to-E isomerization of exo-glycals bearing an electron-withdrawing group (EWG). The scope of this novel transformation regarding the carbohydrate unit is also discussed. After elucidating the mechanism, preparation of novel (E)-exo- glycals was performed (TBS = tert-butyldimethylsilyl).

[Study on the chemical constituents of Humulus scandens].

OBJECTIVE: To study the chemical constituents of Humulus scandens. METHODS: The compounds were isolated by column chromatography on silica gel and Sephadex LH-20. The structures were identified by means of IR, 1H-NMR,13C-NMR and MS analyses. RESULTS: Seven compounds were isolated and identified as friedelanone (I), cis-asarone (II), epifriedelanol (III), stigmasta-4-ene-3,6-dione (IV), gamma-sitosterol (V), n-hexadecanoic acid (VI), and linoleic acid (VII), respectively. CONCLUSION: All compounds are isolated from this species for the first time and compounds I - V are obtained from this genus for the first time.