Quinazolinone Research Articles

Synergistic inhibition mechanism of quinazolinone and piperacillin on penicillin-binding protein 2a: a promising approach for combating methicillin-resistant Staphylococcus aureus

The production of penicillin-binding protein 2a (PBP2a), a cell wall synthesis protein, is primarily responsible for the high-level resistance observed in methicillin-resistant Staphylococcus aureus (MRSA). PBP2a exhibits a significantly reduced affinity for most β-lactam antibiotics owing to its tightly closed active site. Quinazolinones (QNE), a novel class of non-β-lactam antibiotics, could initiate the allosteric regulation of PBP2a, resulting in the opening of the initially closed active pocket. Based on our previous study, we have a basic understanding of the dual-site inhibitor ceftaroline (CFT) induced allosteric regulation of PBP2a. However, there are still limitations in the knowledge of how combining medicines, QNE and piperacillin (PIP), induce the allosteric response of PBP2a and inhibit its function. Herein, molecular dynamics (MD) simulations were performed to elucidate the intricate mechanisms underlying the combination mode of QNE and PIP. Our study successfully captured the opening process of the active pocket upon the binding of the QNE at the allosteric site, which alters the signaling pathways with a favorable transmission to the active site. Subsequent docking experiments with different conformational states of the active pocket indicated that all three inhibitors, PIP, QNE, and CFT, exhibited higher docking scores and more favorable docking poses to the open active pocket. These findings reveal the implied mechanism of QNE-mediated allostery underlying combination therapy and provide novel insights into developing innovative therapeutic modalities against MRSA. Communicated by Ramaswamy H. Sarma

A Pseudomonas aeruginosa PQS quorum-sensing system inhibitor with anti-staphylococcal activity sensitizes polymicrobial biofilms to tobramycin

SummaryAs single- and mixed-species biofilms, Staphylococcus aureus and Pseudomonas aeruginosa cause difficult-to-eradicate chronic infections. In P. aeruginosa, pseudomonas quinolone (PQS)-dependent quorum sensing regulates virulence and biofilm development that can be attenuated via antagonists targeting the transcriptional regulator PqsR (MvfR). Here, we exploited a quinazolinone (QZN) library including PqsR agonists and antagonists for their activity against S. aureus alone, when co-cultured with P. aeruginosa, and in combination with the aminoglycoside tobramycin. The PqsR inhibitor, QZN 34 killed planktonic Gram-positives but not Gram-negatives. QZN 34 prevented S. aureus biofilm formation, severely damaged established S. aureus biofilms, and perturbed P. aeruginosa biofilm development. Although P. aeruginosa protected S. aureus from tobramycin in mixed biofilms, the combination of aminoglycoside antibiotic with QZN 34 eradicated the mixed-species biofilm. The mechanism of action of QZN 34 toward Gram-positive bacteria is shown to involve membrane perturbation and dissipation of transmembrane potential.

Quasi-homogeneous catalytic conversion of CO2 into quinazolinones inside a metal–organic framework microreactor

Management of CO2 has been attracting great attention in this century.

Studies on fragment-based design of allosteric inhibitors of human factor XIa

Human factor XIa (hFXIa) has emerged as an attractive target for development of new anticoagulants that promise higher level of safety. Different strategies have been adopted so far for the design of anti-hFXIa molecules including competitive and non-competitive inhibition. Of these, allosteric dysfunction of hFXIa’s active site is especially promising because of the possibility of controlled reduction in activity that may offer a route to safer anticoagulants. In this work, we assess fragment-based design approach to realize a group of novel allosteric hFXIa inhibitors. Starting with our earlier discovery that sulfated quinazolinone (QAO) bind in the heparin-binding site of hFXIa, we developed a group of two dozen dimeric sulfated QAOs with intervening linkers that displayed a progressive variation in inhibition potency. In direct opposition to the traditional wisdom, increasing linker flexibility led to higher potency, which could be explained by computational studies. Sulfated QAO 19S was identified as the most potent and selective inhibitor of hFXIa. Enzyme inhibition studies revealed that 19S utilizes a non-competitive mechanism of action, which was supported by fluorescence studies showing a classic sigmoidal binding profile. Studies with selected mutants of hFXIa indicated that sulfated QAOs bind in heparin-binding site of the catalytic domain of hFXIa. Overall, the approach of fragment-based design offers considerable promise for designing heparin-binding site-directed allosteric inhibitors of hFXIa.

Facile synthesis of extended TPA-quinazolinone derivatives and the nonlinear optical properties

In this work, four new quinazolinone (QZ)-based compounds containing triphenylamine (TPA) moiety have been synthesized, defined as QZC, QZC-1, QZC-2, QZC-3, for the application of third-order nonlinear optical (NLO) responses. A new design of two-step synthesis has been put forward, the first step is Ullmann reaction with QZ, and the second is connecting QZ and the substituted triphenylamines (TPAs) through a Suzuki cross-coupling reaction to afford the target products. Electrochemical measurement data indicated that the tuning of the HOMO and LUMO energy levels can be easily achieved by introducing and modifying the donor moiety. The NLO properties were evaluated by the Z-scan technique which showed that introduction of a benzene ring as a π bridge could reduce the transmission energy of electrons from a ground state to an excited state, and the added methoxy in TPA moiety could promote the ICT, and improve the third-order NLO properties of molecules. Theoretical calculations matched well with the electrochemical information and NLO information. The results suggest that the materials based on QZ have potential applications in integrated NLO devices.

Enantioselective N–H Functionalization of Quinazolinones

Key words N–H functionalization - quinazolines - allenes - allylic carbonates - rhodium catalysis - allylation

A Quinazolinone Derivative-based Fluorescent Probe for Hypochlorite Ion Recognition

A Quinazolinone Derivative-based Fluorescent Probe for Hypochlorite Ion Recognition

Production of Secondary Metabolites from Two Penicillium StrainsAdapted to Different Temperature Conditions: A Study on DifferentialResponse of Fungal Strains to Temperature Stress

In the present investigation, temperature dependent production of secondary metabolites of two Penicillium strains i.e., cold tolerant Penicillium oxalicum originally isolated from a low temperature environment of Leh (Ladakh), India and the other one is mesophilic Penicillium citrinum (KR150257) isolated from Lucknow (Uttar Pradesh), India. The psychrotolerant P. oxalicum can grow at low temperature (4°C) and shows optimum growth at 15°C, while the mesophilic P. citrinum exhibits optimum growth temperature at 35°C. The study of secondary metabolites produced by both Penicillium strains, studied by UV-Visible Spectroscopy, GC-MS, confirmed the presence of alkaloids, mycotoxins, antibiotics, hydrocarbons and fatty acids. The maximum production of alkaloids by cold tolerant Penicillium oxalicum is detected under temperature stress (35°C). On the other hand, mesophilic Penicillium citrinum produced maximum alkaloids with different absorption characteristics at 35°C. The GC-MS analysis of secondary metabolites revealed the presence of number of unique biochemical compounds in both the P. oxalicum and P. citrinum strains grown under temperature stress conditions (35°C and 4°C, respectively). The common biochemical in the secondary metabolites produced by both the Penicillium strains grown under temperature stress condition are 3-dodecene, 2-dodecanol and 1-hexadecanol, eicosane, dibutyl, phthalate, 9-hexacosene, propanoic acid, 2-(aminooxy). The three-unique biochemical produced by P. oxalicum grown at low temperature (4°C) are 4(1H) Quinazolinone, 1,4,8-Metheno-1H-cyclopent [f] azulene, 3a, 4, 4a, 7, 7a, 8, 9, 9a-octahydro and 6-Quinazolinol. The five-unique biochemical produced by P. oxalicum at high temperature (35°C) are 2-Methyl-2-propylmethylphospho nofluoridate, Pyridine, 2[(1,1dimethylethyl) thio, 4(1H) Pyrimidinone,6-amino-2-methyl-5-nitroso, 4(3H) Quinolinone and Phthalic acid, di(2-propylpentyl). The seven unique biochemical produced by P. citrinum at low temperature (4°C) are Cyclohexanone, 4-ethyl-4-methyl-3-(1-methylethyl)-,trans-, 3-Methyl-1,4diazabicyclo[4.3.0]nonan-2,5- dione, N-acetyl, Glycyl-L-proline, Pyrrolo [1,2-a]pyrazine-1,4-dione,hexahydro-3-(2-methylpropyl)-, 2,2-Dimethylpropyl 2,2-dimethyl-propanesulfinyl sulfone, 11,14-Eicosadienoic acid, methyl ester. The unique derivative of β-lactam antibiotic produced by the P. citrinum at 35°C is 2,4-Azetidinedione,3,3-diethyl-1-methyl.

Synthesis of 4(3H)-Quinazolinones by Using a CuCO3–K2CO3 Nanocomposite

Synthesis of 4(3H)-Quinazolinones by Using a CuCO3–K2CO3 Nanocomposite

SYNTHESIS OF 3-SUBSTITUTED 4(3 H )-QUINAZOLINONES CATALYSED BY CERIC AMMONIUM NITRATE

The synthesis of 3-substituted 4(3 H )-quinazolinones from anthranilic acid, orthoesters, and amines in the presence of ceric ammonium nitrate has been studied. The reaction occurred in a few minutes at room temperature under solvent-free conditions and in excellent yields. The probable conversion mechanism has been discussed. How to Cite Wang, M.; Song, Z. G.; Zhang, T. T. Chem. Heterocycl. Compd. 2010 , 46 , 581. [ Khim. Geterotsikl. Soedin. 2010 , 733.] For this article in the English edition see DOI 10.1007/s10593-010-0548-4

ChemInform Abstract: Highly Efficient Four‐Component Synthesis of 4(3H)‐Quinazolinones: Palladium‐Catalyzed Carbonylative Coupling Reactions.

AbstractA novel Pd‐catalyzed four‐component carbonylative‐coupling for the construction of N‐substituted 4(3H)‐quinazolinones in a one‐pot manner is presented.

Structural Basis for Native Agonist and Synthetic Inhibitor Recognition by the Pseudomonas aeruginosa Quorum Sensing Regulator PqsR (MvfR)

Bacterial populations co-ordinate gene expression collectively through quorum sensing (QS), a cell-to-cell communication mechanism employing diffusible signal molecules. The LysR-type transcriptional regulator (LTTR) protein PqsR (MvfR) is a key component of alkyl-quinolone (AQ)-dependent QS in Pseudomonas aeruginosa. PqsR is activated by 2-alkyl-4-quinolones including the Pseudomonas quinolone signal (PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone), its precursor 2-heptyl-4-hydroxyquinoline (HHQ) and their C9 congeners, 2-nonyl-3-hydroxy-4(1H)-quinolone (C9-PQS) and 2-nonyl-4-hydroxyquinoline (NHQ). These drive the autoinduction of AQ biosynthesis and the up-regulation of key virulence determinants as a function of bacterial population density. Consequently, PqsR constitutes a potential target for novel antibacterial agents which attenuate infection through the blockade of virulence. Here we present the crystal structures of the PqsR co-inducer binding domain (CBD) and a complex with the native agonist NHQ. We show that the structure of the PqsR CBD has an unusually large ligand-binding pocket in which a native AQ agonist is stabilized entirely by hydrophobic interactions. Through a ligand-based design strategy we synthesized and evaluated a series of 50 AQ and novel quinazolinone (QZN) analogues and measured the impact on AQ biosynthesis, virulence gene expression and biofilm development. The simple exchange of two isosteres (OH for NH2) switches a QZN agonist to an antagonist with a concomitant impact on the induction of bacterial virulence factor production. We also determined the complex crystal structure of a QZN antagonist bound to PqsR revealing a similar orientation in the ligand binding pocket to the native agonist NHQ. This structure represents the first description of an LTTR-antagonist complex. Overall these studies present novel insights into LTTR ligand binding and ligand-based drug design and provide a chemical scaffold for further anti-P. aeruginosa virulence drug development by targeting the AQ receptor PqsR.

Synthesis of Some Heterocyclic Molecuoles from New Benzoxazinones and Quinazolinones

Synthesis of Some Heterocyclic Molecuoles from New Benzoxazinones and Quinazolinones

ChemInform Abstract: Yb(OTf)3 Catalyzed New Cascade Reaction: A Facile Assembly of Fused Quinazolinones.

ChemInform Abstract: Yb(OTf)₃ Catalyzed New Cascade Reaction: A Facile Assembly of Fused Quinazolinones.

ChemInform Abstract: Non-Steroidal Antiinflammatory Agents. Synthesis of Novel 2-Pyrazolyl- 4(3H)-quinazolinones.

Four novel series of pyrazolyl-4(3H)-quinazolinones have been prepared through the reaction of 3-aryl-2-hydrazino-4(3H)-quinazolinones with antipyrylazo-derivatives of ethyl acetoacetate, acetylacetone or diethyl malonate. These series of compounds are 3-aryl-2-[1-ethoxycarbonyl-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - pyrazol-4-yl)hydrazono-2-propylidene]hydrazino-4(3H)-quinazo linones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-4(3H)-quinaz olinones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)azo -3,5- dimethyl-1H-pyrazol-1-yl]-4(3H)-quinazolinones and 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3,5-dioxo-pyrazolidin-2-yl]-4(3H)-quinazolinones. The antiinflammatory activity of some representatives of the prepared compounds was studied.

ChemInform Abstract: Quinazolinones. Part 2. Synthesis of 2-(4-Benzylpiperazin-1-ylmethyl)- 2,3-dihydro-5H-oxazolo(2,3-b)quinazolin-5-one and -2,3-dihydro-5H- thiazolo(2,3-b)quinazolin-5-one.

ChemInform Abstract: Quinazolinones. Part 2. Synthesis of 2-(4-Benzylpiperazin-1-ylmethyl)- 2,3-dihydro-5H-oxazolo(2,3-b)quinazolin-5-one and -2,3-dihydro-5H- thiazolo(2,3-b)quinazolin-5-one.

Synthesis of 2-ethynyl-4(3H)quinazolinone and 2-(1,3-butadienyl)-4(3H)quinazolinone

Ethynyl-4(3H)quinazolinone and 2-(1,3-butadienyl)-4(3H)quinazolinone have been synthesized by cyclizations from appropriate precursors. These two molecules are of interest as analogues of the known p-53 reactivator 2-vinyl-4(3H)quinazolinone.

Synthesis of Some Novel 1,3,4‐Oxadiazol‐2‐yl‐4(3H)‐quinazolinones

N‐1‐Aroyl‐2‐{[(3‐methyl‐4(3H)‐quinazolinone‐2‐yl)methyl]anilino} ethano hydrazides (4), prepared from 2‐phenylaminomethyl‐3‐methyl‐4(3H)‐quinazolinone (1), underwent PPA‐catalyzed cyclization the to title compounds 5 in 51–67% yield.

Studies on some biologically active substituted 4(3H)-quinazolinones. Part 1. Synthesis, characterization and anti-inflammatory-antimicrobial activity of 6,8-disubstituted 2-phenyl-3-[substituted-benzothiazol-2-yl]-4(3H)-quinazolinones

Studies on some biologically active substituted 4(3H)-quinazolinones. Part 1. Synthesis, characterization and anti-inflammatory-antimicrobial activity of 6,8-disubstituted 2-phenyl-3-[substituted-benzothiazol-2-yl]-4(3H)-quinazolinones

Metalation of Sulfoxides in the Benzodiazine Series. Diazines. Part 44.

AbstractFor Abstract see ChemInform Abstract in Full Text.