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Relevant academic research and scientific papers

QUINAZOLINONE COMPOUNDS AND RELATED COMPOUNDS

Disclosed are substituted quinazolinone compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions to treat diseases, disorders, or conditions such as those relating to unregulated protein functi

Synthesis and evaluation of new quinazolin-4(3H)-one derivatives as potent antibacterial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis

Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 μg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC50 = >5 μg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4′c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ～2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 μg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC50 = 12.5->100 μg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.

Fluorine-containing heterocycles: Xix. * synthesis of fluorine-containing quinazolin-4-ones from 3,1-benzoxazin-4-ones

Reactions of fluorine-containing 3,1-benzoxazin-4-ones with ammonium acetate, hydrazine, and heteroaromatic amines gave new 3H-, 3-amino-, and 3-hetarylquinazolin-4-ones, respectively. Differences in the conditions of formation of benzoxazinones from anthranilic acids with different fluorination patterns and in the reactions of fluorinated 3,1-benzoxazinones with nitrogen-centered nucleophiles were revealed. Pleiades Publishing, Ltd., 2009.

Synthesis, structure-activity relationships, and biological profiles of a quinazolinone class of histamine H3 receptor inverse agonists

A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H3 receptor inverse agonists. 2-Methyl-3-(4-{[3-(1- pyrrolidinyl)propyl]oxy}phenyl)-5-(trifluoromethyl)-4(3H)-quinazolinone (1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of 1 between human and rodent P-gps, the observed rodent brain permeability of 1 is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.