Quinazolinone Ring Research Articles

Apparent Crazy Paving “Pulmonary Alveolar Proteinosis versus Hypersensitivity Pneumonitis”

Inhibition of soluble epoxide hydrolase (sEH) is considered as a promising target to reduce blood pressure, improve insulin sensitivity, and decrease inflammation. Material and Method: In this study, a series of some novel quinazoline-4(3H)- one derivatives (3a-t) with varying steric and electronic properties was designed, synthesized, and evaluated as sEH Inhibitors (sEHI). Most of the synthesized compounds had similar inhibitory activity to the commercial reference inhibitor, 12-(3-adamantan-1-ylureido) dodecanoic acid, and among them, 4-chloro-N-(4-(4-oxo-3,4-dihy- droquinazoline-2-yl)phenyl)benzamide (3g) was identified as the most active sEHI (IC50 = 0.5 nM), about two-fold more potent compared to the reference inhibitor. Conclusion: The results of molecular modeling followed by biological studies indicate that a quinazolinone ring serves as a suitable scaffold to develop novel small molecule candidates to inhibits EH and the nature of substituent on the amide moiety has a moderate effect on the activity.

Syntheses and Cytotoxicities of Quinazolinone-Based Conjugates.

Two novel series of quinazolinone-based hybrids, including quinazolinone-1,3,4-oxadiazoles (10a-l) and quinazolinone-1,3,4-oxadiazole-benzimidazoles (8a-e), were designed and synthesized and their cytotoxic activities against three human cancer cell lines, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MCF-7), were evaluated. The cytotoxic assays revealed that 10i with a lipophilic 4-fluoro-phenyl moiety at the C-2 position of the quinazolinone ring displayed good cytotoxicities against the A549 and MCF-7 cell lines, while 8b-d with the thioether-linked benzimidazole moiety incorporated on the right side of the oxadiazole ring induced comparable stronger activities toward the MCF-7 cell line, relative to the simple two-heterocycle-containing hybrid 10i. These novel quinazolinone-based hybrids could be considered as lead compounds that merit further optimization and development as anti-cancer agents.

In-silico Studies of Quinazolinone Analogues to Distinguish their Hypothetical Binding Mode using the X-ray crystal Structure Human carbon Anhydrase II (HCAII) Enzyme Complex with Sugar Sulfamate for Anticonvulsant Activity

The quinazolinone moiety is a significant pharmacophore that depicts various types of pharmacological activities as shown in recent exhaustive ligatures. Quinazolinone exhibit potent central nervous system (CNS) activities like anti-anxiety, analgesic, anti-inflammatory and anticonvulsant. To develop these views and application profiles, attempt have been made to report a drug/ligand or receptor/protein interactions by identifying the suitable active site against X-ray crystal structure of Human Carbonic Anhydrase II (HCA II) enzyme for anticonvulsant activity using Vlife MDS version 4.6 Software because the protein-ligand interaction plays a significant role in structural based drug designing. The interaction was evaluated based on the score comparison between quinazolinone derivatives with sugar sulfamate. The quinazolinone ring forms hydrophobic and hydrogen bond contacts amino acid residues. The ligands 4t and 4s were shown to possess minimum dock score i.e. minimum binding energy in Kcal/mole i.e. these molecules has more affinity for the active site of the receptor. Molecules with low dock score and binding energy show more affinity towards the receptor. The data reported in this article may be helpful for the medicinal chemists who are working in this area.

A New Domino Reaction under Microwave Irradiation for the Synthesis of Pyrazolo[5,1-b]quinazolinones

AbstractPyrazolo[5,1-b]quinazolinones were synthesized by consecutive pyrazole and quinazolinone ring closures in a new catalyst-free microwave-promoted domino reaction of hydrazine with 2-cyano-3-(methylthio)-3-(2-methoxycarbonylphenylamino)acrylates, which were prepared from methyl anthranilate and 2-cyano-3,3-bis(methylthio)acrylates. When 2-cyano-3,3-bis(methylthio)acrylates reacted directly with anthranilic acid hydrazide, the arylamino group remained intact, while the hydrazide moiety transformed into 1-acylpyrazoles and further to 2-(1,3,4-oxadiazolylidene)-2-cyanoacetates. The structures of representatives from each group of the prepared heterocyclic compounds were examined in detail by X-ray crystallography.

Divergent Protocol for the Synthesis of Isoquinolino[1,2-b]quinazolinone and Isoquinolino[2,1-a]quinazolinone Derivatives.

The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities. In this context, the development of an efficient strategy for their access is needed. Herein, we report a divergent metal-free operation to access a diverse collection of C6-substituted pyrrolo[4',3',2':4,5]isoquinolino[1,2-b]quinazolin-8(6H)-one and pyrrolo[4',3',2':4,5]isoquinolino[2,1-a]quinazolin-12(6H)-one architectures. The described cascade unites Friedel-Crafts and aza-Michael addition reactions. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the cascade features a promising approach for the design of unique compound libraries for drug design and discovery programs.

Novel Benzoic Acid Derivatives Bearing Quinazolin‐4(3H)‐one Ring: Synthesis, Characterization, and Inhibition Effects on α‐Glucosidase and α‐Amylase

AbstractIn this study, new benzoic acid derivatives of the quinazolinone ring, which is one of the biologically active members of nitrogen‐containing heterocyclic compounds, were synthesized with excellent yields (98–90 %). The structures of the novel compounds (1–12) were characterized with Fourier‐transform Infrared (FTIR), Nuclear Magnetic Resonance (1H NMR–13C NMR), and High‐Resolution Mass Spectroscopy (HRMS). α‐Glucosidase and α‐Amylase inhibition properties were examined to evaluate the anti‐diabetic properties of the synthesized compounds. For α‐Glucosidase, molecules showed IC50 in ranging of >100–3.468±0.270 μM and Kis in ranging of >100–3.310±0.326 μM. For α‐Amylase, molecules showed IC50 in ranging of >100–1.215±0.225 μM. 4‐[(2‐[(4‐phenylpiperazin‐1‐yl)methyl]‐4‐oxoquinazolin‐3(4H)‐ylimino)methyl]benzoicacid (10) has the strongest inhibitory effect for both enzymes. It is 5.4 times more potent inhibitor for α‐Glucosidase and 34.9 times more potent for α‐Amylase than the standard inhibitor Acarbose. Also, the molecular docking study was carried out for the most active compound for the determination of ligand‐enzyme interactions. Binding affinities of the most active compound were calculated as −5.978 kcal/mol and −5.548 kcal/mol for α‐Glucosidase and α‐Amylase, respectively. The aromatic ring and the aminomethyl group of the quinazoline and the carboxyl group moieties have played a critical role in the inhibition.

New quinazolinone-based derivatives as DHFR/EGFR-TK inhibitors: Synthesis, molecular modeling simulations, and anticancer activity.

New 2-mercapto-quinazolin-4-one analogs were synthesized and tested for their in vitro anticancer activity, dihydrofolate reductase (DHFR) inhibition, and epidermal growth factor tyrosine kinase (EGFR-TK) inhibition activities. Compound 24, which is characterized by a 2-benzyl-thio function, showed broad-spectrum anticancer activity with high safety profile and selectivity index. The concentrations of 24 causing 50% growth inhibition (GI50 ) and total cell growth inhibition (TGI) and its lethal concentration 50 (LC50 ) were 15.1, 52.5, and 91.2 µM, respectively, using 5-fluorouracil as a positive control. Also, it showed EGFR-TK inhibitory activity with IC50 = 13.40 nM compared to gefitinib (IC50 = 18.14 nM) and DHFR inhibitory potency with 0.30 μM compared to methotrexate (MTX; IC50 = 0.08 μM). In addition, compound 24 caused cell cycle arrest and apoptosis on COLO-205 colon cancer cells. Compounds 37, 21, and 54 showed remarkable DHFR inhibitory activity with IC50 values of 0.03, 0.08, and 0.08 μM, respectively. The inhibitory properties of these compounds are due to an electron-withdrawing group on the quinazolinone ring, except for compound 54. In a molecular modeling study, compound 24 showed the same binding mode as gefitinib as it interacted with the amino acid Lys745 via π-π interaction. Compound 37 showed a similar binding mode as MTX through the binding interaction with Lys68, Asn64 via hydrogen bond acceptor, and Phe31 via arene-arene interaction. The obtained model and substitution pattern could be used for further development.

A rapid construction of 4(3H)-quinazolinone and related ring under ultrasound irradiation: In silico/in vitro studies of compounds synthesized

Because of importance of the quinazolinone framework particularly in medicinal and pharmaceutical chemistry efforts have been devoted to establish convenient methods for the synthesis of quinazolinone derivatives. Due to our interest in this class of compounds as potential inhibitor chorismate mutase (MtbCM), a known target for the identification of anti-tubercular agents we report the rapid construction of 4(3H)-quinazolinone ring under ultrasound irradiation. The current sonochemical approach involved an iodine mediated reaction of 2-aminobenzamide or its derivatives with readily available alcohols in aqueous DMSO under ultrasound. A series of 4(3H)-quinazolinone derivatives were prepared where substituents like aryl or heteroaryl ring or an alkyl or styryl moiety can be present at the C-2 position of the product. The analogues of quinazolinone such as pteridin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives were also prepared using this sonochemical approach. Generally, a good yield of product was obtained when the C-2 substituent of the product was an arene moiety whereas the yield was acceptable to moderate in rest of the cases. The use of milder condition, inexpensive iodine as well as aqueous media and shorter duration seemed to be key features of this methodology. The in silico docking studies indicated 3d, 3n and 3u as possible inhibitors that showed H-bonding with the residues ASP69 and GLU106 and a common pi-alkyl interaction with the critical dimer interface residue ARG103 of MtbCM. When tested in vitro against MtbCM these compounds exhibited good activities (> 50% inhibition). The brief Structure-Activity-Relationship (SAR) study indicated beneficial effects of the C-2 substituent in the order benzene > pyridine > indole ring.

Synthesis of Eleven-Membered Cyclic Urea Fused Quinazolinones

AbstractStraightforward synthesis of quinazolinones having N-fused medium-sized ring urea was accomplished. Key intermediates were tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates derived from copper-catalyzed domino reaction of tert-butyl [2-(2-iodobenzamido)ethyl]carbamates and cyclic enaminones. Steric hindrance of cyclic enaminones played an important role in the formation of quinazolinone ring. The eleven-membered ring urea moiety was readily achieved by direct cyclization using 1,1′-carbonyldiimidazole (CDI) of diamino intermediate generated by readily reductive amination and deprotection of tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates.

Synthesis and Evaluation of Antioxidant Properties of 2-Substituted Quinazolin-4(3H)-ones.

Quinazolinones represent an important scaffold in medicinal chemistry with diverse biological activities. Here, two series of 2-substituted quinazolin-4(3H)-ones were synthesized and evaluated for their antioxidant properties using three different methods, namely DPPH, ABTS and TEACCUPRAC, to obtain key information about the structure–antioxidant activity relationships of a diverse set of substituents at position 2 of the main quinazolinone scaffold. Regarding the antioxidant activity, ABTS and TEACCUPRAC assays were more sensitive and gave more reliable results than the DPPH assay. To obtain antioxidant activity of 2-phenylquinazolin-4(3H)-one, the presence of at least one hydroxyl group in addition to the methoxy substituent or the second hydroxyl on the phenyl ring in the ortho or para positions is required. An additional ethylene linker between quinazolinone ring and phenolic substituent, present in the second series (compounds 25a and 25b), leads to increased antioxidant activity. Furthermore, in addition to antioxidant activity, the derivatives with two hydroxyl groups in the ortho position on the phenyl ring exhibited metal-chelating properties. Our study represents a successful use of three different antioxidant activity evaluation methods to define 2-(2,3-dihydroxyphenyl)quinazolin-4(3H)-one 21e as a potent antioxidant with promising metal-chelating properties.

Discovery of novel heterocyclic amide-based inhibitors: an integrative in-silico approach to targeting soluble epoxide hydrolase

Inhibition of soluble epoxide hydrolase (sEH) is considered as an emerging druggable target to reduce blood pressure, improve insulin sensitivity, and decrease inflammation. Despite the availability of different classes of sEH small molecule inhibitors for the potential treatment of hypertension, only a few candidates have reached clinical trials, making the optimal control of blood pressure presently unattainable. This necessity motivated us to explore a series of novel quinazoline-4(3H)-one and 4,6-disubstituted pyridin-2(1H)-one derivatives targeting sEH enzyme. Herein, comprehensive computational investigations were performed to probe the inhibition efficacy of these potent compounds in terms of inhibitor-enzyme interactions against sEH. In this study, the 39 in-house with a focused library comprising 39 in-house synthesized compounds were selected. The structure-based pharmacophore modeling was developed based on the crystal structure of sEH with its co-crystallized biologically active inhibitor. The generated hypotheses were applied for virtual screening-based PHASE fitness scores. Docking-based virtual screening workflows were used to generate lead compounds using HTVS, SP and XP based GLIDE G-score values. The candidate leads were filtered using ADMET pharmacological and physicochemical properties screening. A 100-ns of molecular dynamics simulations with Molecular dynamics simulations (100 ns) were performed to explore the binding affinities of the considered compounds. Our study identified four best candidates from quinazoline-4(3H)-one derivatives, which indicated that a quinazolinone ring serves as a suitable scaffold to develop novel small molecule sEH inhibitors.

Synthesis and in vitro antileishmanial efficacy of novel quinazolinone derivatives.

Currently available drugs being used to treat leishmaniasis have several shortcomings, including high toxicity, drug administration that requires hospitalization, and the emergence of parasite resistance against clinically used drugs. As a result, there is a dire need for the development of new antileishmanial drugs that are safe, affordable, and efficient. In this study, two new series of synthesized quinazolinone derivatives were investigated as potential future antileishmanial agents, by assessing their activities against the Leishmania (L.) donovani and L.major species. The cytotoxicity profiles of these derivatives were assessed in vitro on Vero cells. The compounds were found to be safer and without any toxic activities against mammalian cells, compared to the reference drug, halofuginone, a clinical derivative of febrifugine. However, they had demonstrated poor antileishmanial growth inhibition efficacies. The two compounds that had been found the most active were the mono quinazolinone 2d and the bisquinazolinone 5b with growth inhibitory efficacies of 35% and 29% for the L.major and L.donovani 9515 promastigotes, respectively. These outcomes had suggested structural redesign, inter alia the inclusion of polar groups on the quinazolinone ring, to potentially generate novel quinazolinone derivatives, endowed with effective antileishmanial potential.

Design and Molecular Docking Studies of Some 2,3 Di-Substituted Quinazolin-4-One Analogues Against Staphylococcus aureus UDG.

In this present investigation, some 2, 3 disubstituted-quinazolin-4-one derivatives are designed and docked against chain A and chain B of (3WDF) receptor. The heterocyclic fused rings quinazolinone have drawn a great attention owing to their expanded applications in the field of pharmaceutical chemistry. The diverse range of molecules with quinazoline/quinazolinone moieties have been reported to exhibit a broad spectrum of biological activities. The results designate that the quinazolinone ring forms hydrophobic and hydrogen bond contacts with ASN 127 A, ALA 126 A, and SER 83 B, SER 183 B amino acid residue. Molecular docking is safe and straightforward to use tool which facilitates in investigating, interpreting, enplaning and identification of molecular properties using 3D structures.

Synthesis, characterization, and investigation of the anti-inflammatory effect of 2,3-disubstituted quinazoline-4(1H)-one

BackgroundQuinazolin-4(1H)-one nucleus has attracted the attention of medicinal chemists due to their clinical uses. Modification of quinazolinone ring for the development of pharmaceutical and clinical compound for its anti-inflammatory potential.ResultsIn vitro anti-inflammatory activity of the synthesized compounds was performed by using egg albumin protein denaturation assay, while in vivo anti-inflammatory activity was performed by using carrageenan-induced rat paw edema and cotton pellet-induced granuloma pouch model.In the present study, we synthesized a new series of 2,3-disubstituted quinazolin-4(1H)-one derivatives and evaluated their in vivo, in vitro anti-inflammatory effect. Their chemical structures are confirmed by FTIR, 1HNMR, and mass spectrum. Among all the synthesized compounds, G1 and G3 exhibit the significant anti-inflammatory activity by inhibiting release of inflammatory mediators like prostaglandin, histamine, and serotonin. in both in vivo and in vitro models as compared to compound G2.ConclusionThese synthesized compounds showed anti-inflammatory activity by inhibiting prostaglandins and COX enzymes. So, all test compounds may be used for both inflammation as well as inflammation-induced cancer therapy. Future various screening method related with inflammation and inflammation-induced cancer needs to be evaluated pre-clinically and clinically.

Rhodium-Catalyzed Merging of 2-Arylquinazolinone and 2,2-Difluorovinyl Tosylate: Diverse Synthesis of Monofluoroolefin Quinazolinone Derivatives.

An efficient method for the synthesis of 2-(o-monofluoroalkenylaryl)quinazolinone derivatives was developed. In this context, the quinazolinone ring served as the inherent directing group, 2,2-difluorovinyl tosylate was used as the monofluoroolefin synthon, and Rh(III)-catalyzed C–H bond difluorovinylation of 2-arylquinazolinons was performed to give the corresponding monofluoroalkene-containing quinazolinons in yields of 65–92%. The method is characterized by broad synthetic utility, mild conditions, and high efficiency.

Microwave Reaction Improved Heterocyclization of Quinazolinone Ring in Synthesis of Erlotinib Analogues

Background Tinibs were a kind of important epidermal growth factor receptor (EGFR) inhibitors used as potential therapeutic agents in treating non-small cell lung cancer (NSCLC) in clinic. The drug resistance of clinical used tinibs made the development of more active tinib analogues an attractive field in research. Quinazoline ring was regarded as the key fragment in tinibs and was indispensible intermediate in the synthesis of quinazoline. Thus, synthesis of intermediates was a key step which would further limit the overall yield of final product of tinib analogues. However, the commonly used synthetic scheme was somewhat complicated and time consuming with relatively low yield in heterocylization of and its derivatives. Aim In this work, we intended to explore an effective way to improve synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5), the key fragment of erlotinib analogues, in both reaction procedure and yield, thus to provide reference to synthesis of other derivatives. Methods A simple microwave-assisted one-pot reaction was employed to improve the synthesis of heterocyclization of ring. The reaction conditions, including microwave power, temperature and time of reaction, were screened to achieve high yield under simple operation. Results 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5) was successfully synthesized from starting material of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile by microwave reaction, which was finished in 1 hour just by one step. The yield of heterocyclization was increased from 29.8% of commonly used three-step scheme to 50% herein. Conclusion Microwave reaction efficiently improved synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one into quinazolinone in both synthetic procedure and yield. The results may provide valuable reference to synthesis of other derivatives.

Quinazoline-4(3H)-one derivatives as novel and potent inhibitors of soluble epoxide hydrolase: Design, synthesis and biological evaluation.

Inhibition of soluble epoxide hydrolase (sEH) is considered as a promising target to reduce blood pressure, improve insulin sensitivity, and decrease inflammation. In this study, a series of some novel quinazoline-4(3H)-one derivatives (3a-t) with varying steric and electronic properties was designed, synthesized and evaluated as sEH Inhibitors. Most of the synthesized compounds had similar inhibitory activity to the commercial reference inhibitor, 12-(3-adamantan-1-ylureido)dodecanoic acid, and amongst them, 4-chloro-N-(4-(4-oxo-3,4-dihydroquinazoline-2-yl)phenyl)benzamide (3g) was identified as the most active sEH inhibitor (IC50=0.5nM), about 2-fold more potent compared to the reference inhibitor. The results of molecular modeling followed by biological studies indicate that a quinazolinone ring serves as a suitable scaffold to develop novel small molecule candidates to inhibit sEH and the nature of substituent on the amide moiety has a moderate effect on the activity.

Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives.

The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-component reaction from 3-amino-4-hydroxycoumarin, isatoic anhydride and benzaldehyde derivatives. In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well. Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation.

The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones. Thienopyrimidinones were found toxic and styryl quinolinones were found inactive. Ethynyl styryl quinazolinone 39 and styryl quinazolinone 5 were found active on par with the earlier reported analogues 1 and 2 suggesting that the 5-nitro furan-2-yl styryl quinazolinones find a real promise in leukemic cell differentiation. The improved potency of 5 suggested that further modifications in the 5-nitro furan-2-yl styryl quinazolinones can be at the phenyl substitution at the 3-position of the quinazolinone ring apart from the 5-position of the heteroaryl ring.

Synthesis of an Activatable Tetra-Substituted Nickel Phthalocyanines-4(3H)-quinazolinone Conjugate and Its Antibacterial Activity.

The aim of this study was to synthesize a series of nickel(II)phthalocyanines (NiPcs) bearing four 4(3H)-quinazolinone ring system units, (qz)4NiPcs 4a–d. The electronic factors in the 4(3H)-quinazolinone moiety that attached to the NiPc skeleton had a magnificent effect on the antibacterial activity of the newly synthesized (qz)4NiPcs 4a–d against Escherichia coli. The minimum MICs and MBCs value were recorded for compounds 4a, 4b, 4c, and 4d, respectively. The results indicated that the studied (qz)4NiPcs 4a–d units possessed a broad spectrum of activity against Escherichia coli. Their antibacterial activities were found in the order of 4d > 4c > 4b > 4a against Escherichia coli, and the strongest antibacterial activity was achieved with compound 4d.