1031-88-5Relevant academic research and scientific papers
Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3 H)-ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis
Atobe, Masakazu,Nagami, Takamichi,Muramatsu, Shuji,Ohno, Takeshi,Kitagawa, Masayuki,Suzuki, Hiroko,Ishiguro, Masashi,Watanabe, Atsushi,Kawanishi, Masashi
, p. 1468 - 1483 (2019)
Osteoarthritis (OA) is a degenerative disease characterized by joint destruction and loss of cartilage. There are many unmet needs in the treatment of OA and there are few promising candidates for disease-modifying OA drugs, particularly, anabolic agents. Here, we describe the identification of novel quinazolin-4(3H)-one derivatives, which stimulate chondrocyte cartilage matrix production via TRPV4 and mitigate damaged articular cartilage. We successfully identified the water-soluble, highly potent quinazolin-4(3H)-one derivative 36 and studied its intra-articular physicochemical profile to use in in vivo surgical OA model studies. Compound 36·HCl provided relief from OA damage in a rat medial meniscal tear (MT) model. Specifically, 36·HCl dose-dependently suppressed cartilage degradation and enhanced the messenger RNA expression of aggrecan and SOX9 in cartilage isolated from MT-operated rat knees compared with knees treated with vehicle. These results suggest that 36 induces anabolic changes in articular cartilage and consequently reduces OA progression.
Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazolin-4(3H)-one derivatives as potential PPARγ and SUR agonists
Ibrahim, Mohamed K.,Eissa, Ibrahim H.,Alesawy, Mohamed S.,Metwaly, Ahmed M.,Radwan, Mohamed M.,ElSohly, Mahmoud A.
, p. 4723 - 4744 (2017)
Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARγ binding affinities and insulin-secreting abilities. Compounds 19b, 19d, 19f, 25f and 25g exhibited the highest affinities against PPARγ with IC50 values of 0.371, 0.350, 0.369, 0.408 and 0.353 μM, respectively. In addition, compounds 19d, 19f, and 25d showed the highest insulin-secreting activities with EC50 values of 0.97, 1.01 and 1.15 μM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARγ and SUR.
Design and synthesis of new benzylidene-quinazolinone hybrids as potential anti-diabetic agents: In vitro α-glucosidase inhibition, and docking studies
Ayyad, Rezk R.,Ibrahim, Albaraa,Khalifa, Mohamed M.,Mansour, Ahmed M.,Sakr, Helmy M.
, (2021/11/08)
A novel series of benzylidene-quinazolinone hybrids 8a,b and 10a-n were designed, synthesized, and evaluated for their in vitro α-glucosidase inhibitory effect aiming to discover efficient anti-diabetic agents. The synthesized compounds were assessed for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Five compounds (10m, 10f, 10c, 10d and 8b) demonstrated potent activities with percent reduction in blood glucose levels of 43.07, 40.14, 39.83, 37.04 and 36.16, respectively. The most active members were further evaluated in vitro for their α-glucosidase inhibitory binding affinities. Among them, Compound 10m containing 4-hydroxybenzylidene moiety and compound 10f with 4-chlorobenzylidene moiety connected to the acetohydrazide demonstrated the most potent inhibitory activities towards α-glucosidase with IC50 values of 561 and 610 μM, respectively. Molecular docking study was performed in order to understand the molecular interactions between the molecule and enzyme.
Design, synthesis, biological evaluation, and molecular docking study of thioxo-2,3-dihydroquinazolinone derivative as tyrosinase inhibitors
Adibi, Hossein,Asgari, Mohammad Sadegh,Attarroshan, Mahshid,Farid, Sara Moghadam,Hamedifar, Haleh,Hosseini, Samanesadat,Iraji, Aida,Kabiri, Maryam,Khoshneviszadeh, Mehdi,Larijani, Bagher,Mahdavi, Mohammad,Moayedi, Seyedeh Sara,Moazzam, Ali,Pirhadi, Somayeh,Sakhteman, AmirHossein,Sepehri, Nima
, (2022/01/11)
Tyrosinase is known to be a key enzyme in melanogenesis and hyperpigmentation. In this study, a series of thioxo-dihydroquinazolinone compounds were designed and synthesized as tyrosinase inhibitors. Among the investigated compounds, 4m demonstrated the best inhibitory activity with an IC50 value of 15.48 μM compared to kojic acid as a positive control with IC50 value of 9.30 μM. In kinetic evaluation against tyrosinase, 4m depicted a mixed inhibition pattern. Additionally, antioxidant evaluations exhibited moderate to weak potency in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The detailed interactions and binding mode toward tyrosinase of the most potent derivative were explicated by molecular docking study. Moreover, the computer-aided drug-likeness and pharmacokinetic studies were also carried out.
Synthesis, in vitro, and in silico studies of newly functionalized quinazolinone analogs for the identification of potent α-glucosidase inhibitors
Wali, Hayat,Anwar, Ayaz,Shamim, Shahbaz,Khan, Khalid Mohammed,Mahdavi, Mohammad,Salar, Uzma,Larijani, Bagher,Perveen, Shahnaz,Taha, Muhammad,Faramarzi, Mohammad Ali
, p. 2017 - 2034 (2021/01/26)
Functionalized quinazolinone derivatives 1–30 were synthesized by two-step reaction. First, anthranilic acid was treated with substituted phenyl isothiocyanate to synthesize 3-aryl-2-thioxo-2,3-dihydroquinazolinone derivatives 1–8 which in turn reacted with different bromoacetophenone derivatives to obtain fully functionalized quinazolinone derivatives 9–30. Both reactions were catalyzed by triethylamine. All the products were characterized by EI-, HREI-MS, 1H-, and 13CNMR spectroscopic techniques. All compounds were subjected to their in vitro α-glucosidase inhibitory activity. Results showed that except compound 1–3, 5, 7, and 22, all compounds were found potent and showed many folds increased α-glucosidase enzyme inhibition as compared to standard acarbose (IC50 = 750.0 ± 10.0?μM). Compound 13 (IC50 = 85.0 ± 0.5?μM) was recognized as the most potent analog of the whole series, with ninefold enhanced inhibitory potential than the standard acarbose. Compounds 1–9, 11, 12, 22, and 26 were structurally known compounds, while remaining all are new. Kinetic study on compound 13 showed that the compound is following a competitive-type inhibition mechanism. Furthermore, in silico studies have also been performed to better rationalize the interactions between synthetic compound and active site of the enzyme. Graphic abstract: [Figure not available: see fulltext.]
Synthesis, biological evaluation and molecular docking studies of novel quinazolinones as antitubercular and antimicrobial agents
Kumar Pandey, Sarvesh,Yadava, Umesh,Upadhyay, Anjali,Sharma
, (2021/02/05)
In the present study, a series of novel quinazolinone hybrids, viz. triazepino-quinazolinones 4, thiazolo-triazolo-quinazolinones 7 and triazolo-quinazolinones 8 have been synthesized from the key intermediate 3-(substituted phenyl)-2-hydrazinoquinazolin-4(3H)-ones 3. All the newly synthesized compounds were characterized by means of spectral (IR, 1H NMR, 13C NMR) and elemental analysis. The target compounds were biologically screened for their in vitro antimicrobial and antitubercular activities against pathogenic strain. The results of bioassay demonstrated that some of the compounds exhibited pronounced antimicrobial activity comparable to that of standard drugs tested under similar conditions. Compounds 4c, 4e, 7e and 8b showed relatively very good inhibitory activity against pathogenic bacteria with minimum inhibitory concentration (MIC) of 2.6 μg/mL, 5.2 μg/mL, while the rest of the compounds showed moderate activity. Compounds 4c and 8b were found to be nearly equipotent with ciprofloxacin against P. aeruginosa with MIC 5.2 μg/mL, while compound 8b was more potent against pathogenic bacteria S. aureus. It is very remarkable that four compounds, 4c, 4e, 7e and 8b showed pronounced antifungal activity against selected pathogenic fungi, A. niger, C. albicans with MIC 2.6 μg/mL and 5.2 μg/mL. The antitubercular activity of synthesized compounds reveal that compound 8b showed better activity than the other compounds with a MIC of 5.2 μg/mL against M. tuberculosis (H37Rv). Molecular docking studies of the compounds were performed to rationalize the inhibitory properties of these compounds and results showed that these compounds have good binding energy and better binding affinity within the active pocket, thus these compounds may be considered as potent inhibitors towards selective targets.
The natural-based optimization of kojic acid conjugated to different thio-quinazolinones as potential anti-melanogenesis agents with tyrosinase inhibitory activity
Sepehri, Nima,Iraji, Aida,Yavari, Ali,Asgari, Mohammad Sadegh,Zamani, Saeed,Hosseini, Samanesadat,Bahadorikhalili, Saeed,Pirhadi, Somayeh,Larijani, Bagher,Khoshneviszadeh, Mahsima,Hamedifar, Halleh,Mahdavi, Mohammad,Khoshneviszadeh, Mehdi
, (2021/03/01)
Melanin pigment and melanogenesis are a two-edged sword. Melanin has a radioprotection role while melanogenesis has undesirable effects. Targeting the melanogenesis pathway, a series of kojyl thioether conjugated to different quinazolinone derivatives were designed, synthesized, and evaluated for their inhibitory activity against mushroom tyrosinase. All the synthesized compounds were screened for their anti-tyrosinase activity and all derivatives displayed better potency than kojic acid as the positive control. In this regard, 5j and 5h as the most active compounds showed an IC50 value of 0.46 and 0.50 μM, respectively. In kinetic evaluation against tyrosinase, 5j depicted an uncompetitive inhibition pattern. Designed compounds also exhibited mild antioxidant capacity. Moreover, 5j and 5h achieved good potency against the B16F10 cell line to reduce the melanin content, whilst showing limited toxicity against malignant cells. The proposed binding mode of new inhibitors evaluated through molecular docking was consistent with the results of structure–activity relationship analysis.
Quinazolinone-dihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: Design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic
Sherafati, Maedeh,Mirzazadeh, Roghieh,Barzegari, Ebrahim,Mohammadi-Khanaposhtani, Maryam,Azizian, Homa,Sadegh Asgari, Mohammad,Hosseini, Samanesadat,Zabihi, Ebrahim,Mojtabavi, Somayeh,Ali Faramarzi, Mohammad,Mahdavi, Mohammad,Larijani, Bagher,Rastegar, Hossein,Hamedifar, Haleh,Hamed Hajimiri, Mir
, (2021/02/26)
A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC50 value = 40.1 ± 0.6 μM) with inhibitory activity around 18.75-fold more than acarboase (IC50 value = 750.0 ± 12.5 μM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.
Design, synthesis, in vitro and in silico biological assays of new quinazolinone-2-thio-metronidazole derivatives
Ansari, Samira,Asgari, Mohammad Sadegh,Biglar, Mahmood,Esfahani, Ensieh Nasli,Hamedifar, Haleh,Larijani, Bagher,Mahdavi, Mohammad,Mohammadi-Khanaposhtani, Maryam,Rastegar, Hossein,Tas, Recep,Taslimi, Parham
, (2021/07/08)
A new series of quinazolinone-2-thio-metronidazole derivatives 9a-o was designed, synthesized and assayed for their activities against metabolic enzymes human carbonic anhydrase I and II (hCAs I and II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The results indicated that all the synthesized compounds exhibited excellent inhibitory activities against mentioned enzymes as compared with standard inhibitors. Representatively, the most potent compound against CA enzymes, 4-fluorophenyl derivative 9i, was 4 and 7-times more potent than standard inhibitor acetazolamide against hCA I and II, respectively; 4-fluorobenzyl derivative 9m as the most potent compound against cholinesterase enzymes, was around 11 and 21-times more potent than standard inhibitor tacrine against AChE and BChE, respectively; the most active α-glucosidase inhibitor 9h with 4-methoxyphenyl moiety was 5-times more active that acarbose as standard inhibitor. Furthermore, in order to study interaction modes of the most potent compounds in the active site of their related enzymes, molecular modeling was performed. Druglikeness, ADME, and toxicity profile of the compounds 9i, 9m, and 9h were also predicted.
Anti-HIV and Antibacterial Activities of Novel 2-(3-Substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones
Sulthana,Chitra,Alagarsamy,Saravanan,Solomon, V. Raja
, p. 112 - 121 (2021/04/05)
Abstract: In the present study, we have synthesized a series of novel 2-(3-substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones by the reaction of 3-(substituted)-2-hydrazino-quinazoline-4(3H)-ones with phthalic anhydride. The starting material 3-(substituted)-2-hydrazino-quinazolin-4(3H)-ones were synthesized from various primary amines. All the synthesized compounds were screened for their antitubercular, anti-HIV and antibacterial activity against different gram positive and gram negative strains by agar dilution method. Among the test compounds, 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-dione (QCT7) shown most potent antibacterial activity against E. coli, and S. aureus with the MIC of 3 μg/mL. The compound QCT7 exhibited the antitubercular activity with the MIC of 25 μg/mL and anti-HIV activity with the EC50 of 43.68 μM against HIV1 and HIV2 and offers potential lead for further optimization and development to new antitubercular and anti-HIV agents. The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities and are new scaffolds for antimicrobial activity.
