Synthesis of 3‐aminoalkyl‐2‐arylaminoquiazolin‐4(3H)‐ones and 3,3′‐disubstituted bis‐2‐arylaminoquinazolin‐4(3H)‐ones via reactions of 1‐aryl‐3‐(2‐ethoxycarbonylphenyl)carbodiimides with diamines
TL;DR: In this article, the aza-Wittig reaction of 1-Aryl-3-(2-ethoxycarbonylphenyl)carbo-diimides with primary diamines was characterized and its structure was determined by X-ray crystallography.
About: This article is published in Journal of Heterocyclic Chemistry.The article was published on 2008-09-01. It has received 28 citations till now. The article focuses on the topics: Aryl & Regioselectivity.
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TL;DR: The current review article will briefly outline the new routes and strategies for the synthesis of valuable 4(3H)-quinazolinones.
Abstract: The 4(3H)-quinazolinone is a frequently encountered heterocycle with broad applications including antimalarial, antitumor, anticonvulsant, fungicidal, antimicrobial, and anti-inflammatory. The current review article will briefly outline the new routes and strategies for the synthesis of valuable 4(3H)-quinazolinones.
176 citations
TL;DR: Results indicate that novel arylimine derivatives containing the 4(3H)-quinazolinone moiety can effectively control tobacco bacterial wilt, tomato bacterial wilts, and X. oryzae.
Abstract: Twenty-seven novel (E)-3-[2-arylideneaminoethyl]-2-[4-(trifluoromethoxy)anilino]-4(3H)-quinazolinone derivatives were synthesized by reacting various aromatic aldehydes with intermediate 6. The target compounds were characterized by 1H NMR, 3C NMR, IR, and elemental analysis. Bioassay results revealed that some of the compounds have strong antifungal activities against six fungi (Gibberella zeae, Fusarium oxysporum, Clematis mandshurica, Paralepetopsis sasakii, Phytophthora infestans, and Sclerotinia sclerotiorum) and three bacteria (Xanthomonas oryzae, tomato bacterial wilt, and tobacco bacterial wilt). Notably, these compounds exhibited the highest activity against tomato bacterial wilt and X. oryzae, with 50% effective concentration (EC50) values ranging from 45.96 to 93.31 μg/mL and from 20.09 to 21.33 μg/mL, respectively, which are superior to those of the commercial antibacterial agents thiodiazole-copper (99.80 μg/mL) and bismerthiazol (92.61 μg/mL). These results indicate that novel arylimine deri...
96 citations
TL;DR: Results indicated that novel Schiff base derivatives containing the 4(3H)-quinazolinone moiety can effectively control tobacco and tomato bacterial wilts.
73 citations
Cites methods from "Synthesis of 3‐aminoalkyl‐2‐arylami..."
...According to the reported procedures [23,37], the key intermediates 4ae4d were synthesized by a two-step process, as...
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TL;DR: This review has outlined the extensive application of carbodiimides in the synthesis of N-heterocycles from the 1980s to today.
Abstract: Carbodiimides are a unique class of heterocumulene compounds that display distinctive chemical properties. The rich chemistry of carbodiimides has drawn increasing attention from chemists in recent years and has made them exceedingly useful compounds in modern organic chemistry, especially in the synthesis of N-heterocycles. This review has outlined the extensive application of carbodiimides in the synthesis of N-heterocycles from the 1980s to today. A wide range of reactions for the synthesis of various types of N-heterocyclic systems (three-, four-, five-, six-, seven-, larger-membered and fused heterocycles) have been developed on the basis of carbodiimides and their derivatives.
57 citations
TL;DR: In this article, the iodine-catalyzed reaction of 2-aminobenzamides with 1,3-cyclohexanediones gave structurally diversified products.
28 citations
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TL;DR: It is shown that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group, which results in compounds with enhanced biological properties.
Abstract: A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.
275 citations
TL;DR: The structure-activity data support the presence of a secondary hydrophobic pocket in the vicinity of the primary lipophilic region of the enzyme.
Abstract: A variety of 2,4-dioxoquinazolineacetic acids (10, 11) were synthesized as hybrids of the known aldose reductase inhibitors alrestatin (8), ICI-105,552 (9), and ICI-128,436 (2) and evaluated for their ability to inhibit partially purified bovine lens aldose reductase (in vitro) and their effectiveness to decrease galactitol accumulation in the 4-day galactosemic rat model (in vivo). In support to SAR studies, related analogues pyrimidinediones (12), dihydroquinazolones (13), and indazolidinones (14,15) were synthesized and tested in the in vitro and in vivo assays. All prepared compounds (10-15) have shown a high level of in vitro activity (IC50 approximately 10(-6) to 4 x 10(-8) M). However, only the 2,4-quinazolinedione analogues 10 and 11, with similar N-aralkyl substitution found in 2 and 9, have exhibited good oral potency. The remaining compounds were either inactive or had only a marginal in vivo activity. The structure-activity data support the presence of a secondary hydrophobic pocket in the vicinity of the primary lipophilic region of the enzyme.
264 citations
TL;DR: Isatin (Indole 2,3-dione), its 5-chloro and 5-bromo derivatives were added to 3-amino-2-methylmercapto quinazolin-4(3H)-one to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting with formaldehyde and several secondary amines.
235 citations
TL;DR: High-throughput screening of in-house compound libraries led to the discovery of a novel antibacterial agent, compound 1 (MIC: 12-25 microM against S. pyogenes), which displayed improved broad-spectrum antibacterial activity against a variety of bacterial strains.
Abstract: High-throughput screening of in-house compound libraries led to the discovery of a novel antibacterial agent, compound 1 (MIC: 12-25 microM against S. pyogenes). In an effort to improve the activity of this active compound, a series of 2-substituted quinazolines was synthesized and evaluated in several antibacterial assays. One such compound (22) displayed improved broad-spectrum antibacterial activity against a variety of bacterial strains. This molecule also inhibited transcription/translation of bacterial RNA, suggesting a mechanism for its antibiotic effects. Structure-activity relationship studies of 22 led to the synthesis of another 24 compounds. Although some of these molecules were found to be active in bacterial growth assays, none were as potent as 22. Compound 22 was tested for its ability to cure a systemic K. pneumonia infection in the mouse and displayed moderate effects compared with a control antibiotic, gentamycin.
206 citations
TL;DR: In vitro 20 was superior to fluconazoles, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346, and in vivo 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis.
Abstract: A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure-activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound's half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t1/2 = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.
199 citations