- Reactions of 2-methyl-4H-pyrido[2,3-d][3,1]oxazin-4-one with active methylene compounds: A new efficient route to 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones
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3-Substituted 1,8-naphthyridine-2,4-diones, compounds of very important pharmaceutical use, have been synthesized using a new efficient route. The reaction of 2-methyl-4H-pyrido-[2,3-d][3,1]oxazin-4-one, 1b, with active methylene compounds furnishes the 1-acetyl-3-substituted-4-hydroxy-1,8-naphthyridin-2-ones 3-5, in good yields. In the case of cyanoacetic esters the intermediate C-acylation compounds 7 and 8 were isolated and subsequently cyclized to 1-acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. Spectral data and physical characteristics for all compounds are reported.
- Delieza, Vassiliki,Detsi, Anastasia,Bardakos, Vassilios,Igglessi-Markopoulou, Olga
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- Synthesis and evaluation of new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives as potent antibacterial agents effective against multidrug resistant Staphylococcus aureus
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Treatment of nosocomial and community acquired Staphylococcus aureus infections has become more challenging due to the egression of multi-drug resistance. This has spurred the need for rapid development of new therapeutic agents which can effectively negate the resistance mechanisms. In our current work, several new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives were synthesized and examined for their antimicrobial activity against ESKAP pathogen panel and pathogenic mycobacteria. In the primary screening, compounds 4a, 4b, 6′a, 6′b, 6′h, 6′i and 6′j were found to demonstrate selective and potent inhibitory activity against Staphylococcus aureus (MICs = 0.25–0.5 μg/mL). When tested against Vero cells, all the compounds were found to be non toxic possessing favourable selectivity index (SI > 10), which encouraged us for carrying out further studies. Compound 6′a (SI > 40) was tested against a number of multiple clinical strains of multi-drug resistant S. aureus and was found to exhibit potent activity, irrespective of the resistant status of the strain. Besides, compound 6′a also exhibited concentration dependent bactericidal activity and synergized with the FDA approved drugs tested. The interesting results obtained suggest the potential utility of the newly synthesized compounds for treatment of multidrug resistant S. aureus infections.
- Gatadi, Srikanth,Gour, Jitendra,Shukla, Manjulika,Kaul, Grace,das, Swetarka,Dasgupta, Arunava,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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- Atroposelective Desymmetrization of Resorcinol-Bearing Quinazolinones via Cu-Catalyzed C–O Bond Formation
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Enantioselective Cu-catalyzed C–O cross coupling reactions yielding atropisomeric resorcinol-bearing quinazolinones have been developed. Utilizing a new guanidinylated dimeric peptidic ligand, a set of products were generated in good yields with excellent
- Galls, Alexandra,Miller, Scott J.,Rozema, Soren D.,Yoon, Hyung
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supporting information
p. 762 - 766
(2022/01/28)
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- Chemical Space Exploration around Thieno[3,2- d]pyrimidin-4(3 H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors
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Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection in the United States. Therefore, development of novel treatments for CDI is a high priority. Toward this goal, we began in vitro screening of a structurally diverse in-house library of 67 compounds against two pathogenic C. difficile strains (ATCC BAA 1870 and ATCC 43255), which yielded a hit compound, 2-methyl-8-nitroquinazolin-4(3H)-one (2) with moderate potency (MIC = 312/156 μM). Optimization of 2 gave lead compound 6a (2-methyl-7-nitrothieno[3,2-d]pyrimidin-4(3H)-one) with improved potency (MIC = 19/38 μM), selectivity over normal gut microflora, CC50s > 606 μM against mammalian cell lines, and acceptable stability in simulated gastric and intestinal fluid. Further optimization of 6a at C2-, N3-, C4-, and C7-positions resulted in a library of >50 compounds with MICs ranging from 3 to 800 μM against clinical isolates of C. difficile. Compound 8f (MIC = 3/6 μM) was identified as a promising lead for further optimization.
- Shao, Xuwei,Abdelkhalek, Ahmed,Abutaleb, Nader S.,Velagapudi, Uday Kiran,Yoganathan, Sabesan,Seleem, Mohamed N.,Talele, Tanaji T.
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p. 9772 - 9791
(2019/11/03)
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- Synthesis and evaluation of new quinazolin-4(3H)-one derivatives as potent antibacterial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis
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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.
- Gatadi, Srikanth,Gour, Jitendra,Shukla, Manjulika,Kaul, Grace,Dasgupta, Arunava,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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p. 287 - 308
(2019/05/15)
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- Quinazolinone derivatives as inhibitors of homologous recombinase RAD51
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RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for cancer treatment.
- Ward, Ambber,Dong, Lilong,Harris, Jonathan M.,Khanna, Kum Kum,Al-Ejeh, Fares,Fairlie, David P.,Wiegmans, Adrian P.,Liu, Ligong
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supporting information
p. 3096 - 3100
(2017/06/13)
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- Bicyclic aryl sulphide and aryl sulphoxide derivatives as pest control agent
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The present application relates to new heterocyclic compounds of formula (I) where V is an oxygen, a sulphur or a substituted nitrogen; Q is a substituted carbon or nitrogen; Q1, Q2, Q3, Q4 are each independently of one another a substituted carbon or nit
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Paragraph 0518; 0519; 0520; 0521; 0522
(2016/10/08)
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- 3-(4-ETHYNYLPHENYL) PYRIDOPYRIMIDINONE COMPOUNDS AND PROCESS FOR PREPARATION THEREOF USEFUL AS POTENTIAL ANTIC ANCER AGENTS
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The present invention provides 3-(4-ethynylphenyl) pyridopyrimidinone compounds of formula A as potential anticancer agents. 3-(4-ethynylphenyl) pyridopyrimidinone compounds have shown promising anticancer activity in various cell lines sixty human cancer cell lines.[Formula A] Wherein [Formula B] R1= H, OH, OCH3 R2= H, OH, CH3, OCH3, N02 R3= H, OH, OCH3, F, CI R4= H, OH, CH3, OCH3 R5= H, OH, CH3, OCH3 R6= H, OCH3 R2+R3= -0CH2O-
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Page/Page column 17-33
(2015/03/13)
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- Reactivity of 2-methyl-4H-3,1-benzoxazin-4-ones and 2-methyl-4H-pyrido[2,3- d][1,3]oxazin-4-one under microwave irradiation conditions
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The reactivity of variably substituted 2-methyl-4H-3,1-benzoxazin-4-ones and 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one towards carbon and oxygen nucleophiles under microwave irradiation conditions was investigated. Optimization of the reaction conditions of oxazinones with carbon nucleophiles led to the synthesis of a series of 4-hydroxy-quinolin-2-ones and 4-hydroxy-1,8-naphthyridin-2-ones in high yields, whereas reaction with a variety of alcohols proceeded smoothly to the formation of the corresponding N-acetyl-anthranilates and nicotinates.
- Prousis, Kyriakos C.,Tzani, Andromachi,Avlonitis, Nicolaos,Calogeropoulou, Theodora,Detsi, Anastasia
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p. 1313 - 1321
(2014/01/06)
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- Imidazonaphthyridines
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Imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds induce the biosynthesis of cytokines such as interferon and tumor necrosis factor. The compounds exhibit antiviral and antitumor properties. Methods of preparing the compounds and intermediates useful in the preparation of the compounds are also disclosed.
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- 1H and 13C NMR spectral studies of some 4H-3,1-benzoxazin-4-ones and their 2-acylaminobenzoic acid precursors
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The 1H and 13C NMR spectra of twelve 4H-3,1-benzoxazine-4-ones and of their acylaminobenzoic acid precursors are presented. Differentiation between these two series of compounds is best achieved through the characteristic JCH coupling interactions in the high frequency carbonyl region. Some 4H-pyrido[2,3-d][1,3]oxazin-4-ones have also been studied and some earlier literature assignments revised.
- Osborne, Alan G.,Goolamali, Zia
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p. 1079 - 1100
(2007/10/03)
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- On derivatives of 4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine (author's transl)
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A typical representative of the hypnotic and anticonvulsive 4-quinazoline group is methaqualone (1). A number of new derivatives of 4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine (10) were synthetized by substituting the benzene ring in the quinazolone molecule by the pyridine ring. The synthesis was achieved by the condensation of 2-acetaminonicotinic acid (9) and a primary amine or by the reaction of 2-aminonicotinic acid (8) with acetic acid and a primary amine. These new compounds were tested on animals for antiphlogistic, analgetic and antipyretic activities and for effects on the central nervous system as well. It was tried to establish, on the basis of the results obtained, relations between the chemical constitution and the pharmacological efficacy. It was found that, depending on the nature of the substituents in the position 3; either the antiphlogistic, analgetic and antipyretic effects or the anticonvulsive action will prevail.
- Kretzschmar
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p. 253 - 256
(2007/10/02)
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