- Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)
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Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8 μg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC50 = >10–>100 μg/mL) and exhibited favourable selectivity index (SI = 40–>200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.
- Gatadi, Srikanth,Gour, Jitendra,Kaul, Grace,Shukla, Manjulika,Dasgupta, Arunava,Akunuri, Ravikumar,Tripathi, Richa,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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p. 175 - 183
(2018/08/23)
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- Synthesis of 1,2,3-triazole linked 4(3H)-Quinazolinones as potent antibacterial agents against multidrug-resistant Staphylococcus aureus
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Methicillin and vancomycin resistant Staphylococcus aureus infections are an emerging global health concern leading to increasing morbidity and mortality. Continuous increase in drug resistance has underlined the need for discovery and development of new antibacterial agents acting via novel mechanisms to overcome this pressing issue. In this context, a number of 1,2,3-triazole linked 4(3H)-quinazolinone derivatives were designed and synthesized as potent antibacterial agents. When evaluated against ESKAP pathogen panel, compounds 7a, 7b, 7c, 7e, 7f, 7g, 7h, 7i, 9a, 9c, 9d and 9e exhibited significantly selective inhibitory activities towards Staphylococcus aureus (MIC = 0.5–4 μg/mL). To understand and confirm the specificity of these compounds, the compounds 7a and 9a were tested against E. coli and A. baumannii in combination with sub-lethal concentrations of Polymyxin B nonapeptide (PMBN) and were found to be inactive. This clearly indicated that these compounds possess specific and potent activity towards S. aureus and are inactive against gram-negative pathogens. Encouragingly, the compounds were also found to be non toxic to Vero cells and displayed favourable selectivity index (SI = 40 to 80). Furthermore, 7a and 9a were found to possess potent inhibitory activity when tested against multidrug resistant S. aureus including strains resistant to vancomycin (MIC values 0.5–32 μg/mL), indicating that the compounds are able to escape current drug-resistance mechanisms. With the potent anti-bacterial activity exhibited the new series of 1,2,3-triazole linked 4(3H)-quinazolinones have emerged as promising candidates for treating multidrug resistant Staphylococcus aureus infections.
- Gatadi, Srikanth,Gour, Jitendra,Shukla, Manjulika,Kaul, Grace,Das, Swetarka,Dasgupta, Arunava,Malasala, Satyaveni,Borra, Ramya Sri,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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p. 1056 - 1067
(2018/10/16)
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- Design, synthesis and in vivo screening of some novel quinazoline analogs as anti-hyperlipidemic and hypoglycemic agents
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A novel series of substituted quinazoline derivatives were designed, synthesized and evaluated for their hypolipidemic activity in cholesterol induced hyperlipidemic rats. In vivo screening concluded that compounds A-4, C-5 and C-6 have shown potent antihyperlipidemic activity by decreasing the plasma level of triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), followed by increase in level of high density lipoprotein (HDL).
- Mokale, Santosh N.,Palkar, Akash D.,Dube, Pritam N.,Sakle, Nikhil S.,Miniyar, Pankaj B.
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supporting information
p. 272 - 276
(2016/01/09)
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- Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials
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We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity against Staphylococcus aureus. The first structure-activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model.
- Bouley, Renee,Ding, Derong,Peng, Zhihong,Bastian, Maria,Lastochkin, Elena,Song, Wei,Suckow, Mark A.,Schroeder, Valerie A.,Wolter, William R.,Mobashery, Shahriar,Chang, Mayland
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supporting information
p. 5011 - 5021
(2016/06/13)
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- The reaction of 2-(acylamino)benzonitriles with primary aromatic amines: A convenient synthesis of 2-substituted 4-(arylamino)quinazolines
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Abstract 2-Substituted 4-(arylamino)quinazolines were prepared from 2-(acylamino)benzonitriles and primary arylamines by refluxing in either ethanol using trifluoroacetic acid as a catalyst or acetic acid. The 2-aminobenzonitrile was acylated by reaction with anhydrides, isocyanates, or ethyl chloroformate at room temperature.
- Marinho, Elina,Proen?a, M. Fernanda
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p. 1623 - 1632
(2015/03/30)
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- Quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates: Design, synthesis and biological evaluation as potential anticancer agents
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A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI50 values in the range of 50 values of 0.1 μM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-κB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-κB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.
- Kamal, Ahmed,Vijaya Bharathi,Janaki Ramaiah,Dastagiri,Surendranadha Reddy,Viswanath,Sultana, Farheen,Pushpavalli,Pal-Bhadra, Manika,Srivastava, Hemant Kumar,Narahari Sastry,Juvekar, Aarti,Sen, Subrata,Zingde, Surekha
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experimental part
p. 526 - 542
(2010/04/26)
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- Synthesis, antimalarial and antibacterial activities of 3-amino acid- and aryl amine-substituted 2-methyl- 3H-quinalzolin-4-ones
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A new series of 2-methyl-3H-quinazolinones substituted at the third position with amino acids (2-5) and aryl amine (6, 7) was designed, synthesized, and analyzed by infrared, NMR, and mass spectral analysis. Further, the compounds were screened for their in vivo antimalarial activity using the rodent malaria parasite Plasmodium yoelii (N-67) with the Swiss mice model. The compounds were also tested for their antibacterial activity. Birkhaueser Boston 2009.
- Nainar Meyyanathan, Subramania,Ramu, Mamillapalli,Suresh, Bhojraj
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p. 993 - 999
(2011/12/01)
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- Synthesis, structure-activity relationships, and biological profiles of a quinazolinone class of histamine H3 receptor inverse agonists
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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.
- Nagase, Tsuyoshi,Mizutani, Takashi,Ishikawa, Shiho,Sekino, Etsuko,Sasaki, Takahide,Fujimura, Takashi,Ito, Sayaka,Mitobe, Yuko,Miyamoto, Yasuhisa,Yoshimoto, Ryo,Tanaka, Takeshi,Ishihara, Akane,Takenaga, Norihiro,Tokita, Shigeru,Fukami, Takehiro,Sato, Nagaaki
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supporting information; experimental part
p. 4780 - 4789
(2009/07/25)
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- Fused ring 4-oxopyrimidine derivative
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The present invention provides a compound represented by formula (I) below, or a pharmaceutically acceptable salt thereof, which, having histamine H3 receptor antagonist or inverse agonist activity, is useful in the prophylaxis or therapy of metabolic diseases, circulatory diseases, or nervous system diseases. [where, for example, Ar is a divalent group formed by eliminating two hydrogen atoms from benzene, X1 is a nitrogen atom, sulfur atom or oxygen atom, R1 is a 5- to 6-membered heteroaryl group, Ring A is a 5- to 6-membered heteroaryl ring, R2 and R3 are amino groups or alkylamino groups, and X2 is represented by formula (II): (where R4 and R5 are lower alkyl groups, and n is an integer from 2 to 4).]
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Page/Page column 35
(2008/06/13)
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- Efficient solid phase synthesis of diverse quinazolinones
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Various quinazolinones were synthesized by cyclocondensation of anthranilamides with a variety of orthoformates on solid supports. Alkyl, aryl and alkoxy groups can substitute at 2 position of quinazolines with this method. The reactions proceeded smoothly under mild acidic conditions and the products exhibited excellent purity. Unlike previously reported solid phase quinazolinone syntheses, this synthetic strategy does not require an oxidation step. The approach is applicable to the synthesis of a wide range of quinazolinones, including molecules that are susceptible to oxidation.
- Makino,Suzuki,Nakanishi,Tsuji
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p. 1670 - 1672
(2007/10/03)
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- Synthesis, anti-hypertensive and β-adrenoreceptor antagonist activities of 3--phenyl>-4(3H) quinazolones
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The synthesis of seven 2-substituted 3--phenyl>-4(3H)quinazolones is described.Pharmacological tests showed that some of the synthesized compounds (3a-c and 3e) possessed pronounced and sustained hypotensive effects,
- Botros, Samir,Saad, Samir F.
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p. 585 - 590
(2007/10/02)
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