Dihydrofolate reductase (DHFR) is the important target for anticancer drugs belonging to the class of antimetabolites as the enzyme plays important role in the de novo purine synthesis. We here report the in silico screening to obtain best fit molecules as DHFR inhibitors, synthesis of some 'best fit' quinazolinone from 2-phenyl-3-(substituted-benzilidine-amino) quinazolinones (Quinazolinone Shiff's bases) QSB 1-5 and pyridine-4-carbohydrazide Shiff's bases (ISB 1-5 ) derivatives and their in vitro anticancer assay. Synthesis of the molecules was performed using microwave assisted synthesis. The structures of these molecules were elucidated by IR and 1 H-NMR. These compounds were then subjected for in vitro anticancer evaluation against five human cancer cell-lines for anticancer cyto-toxicity assay. Methotrexate (MTX) was used as standard for this evaluation to give a comparable inhibition of the cell proliferation by DHFR inhibition. Placlitaxel, adriamycin and 5-fluoro-uracil were also used as standard to give a comparable activity of these compounds with other mechanism of anticancer activity. ISB 3 (4-(N, N-dimethyl-amino)-phenyl) Schiff's base derivative of pyridine carbohydrazide showed equipotent activity with the standards used in in vitro anticancer assay as per the NCI (National Cancer Institute) guidelines.
Background: NMDA receptor specifically NR2B subunit plays a major role in eliptogenisis. Antagonists at NR2B receptor site have importance in design of anticonvulsant agents. Some quinazolinones and oxazepine have inherent drug likeliness for anticonvulsant activity. In this research work in silico biological activity spectrum (BAS), ADME prediction, Log P predictions and docking was carried out. A library of quinazolinones with oxazepinone ring was designed, from this library 3-(6-halo-2-methyl-oxoquinazolin-3-(4H-yl)-2-(substituted phenyl)-2, 3-dihydro-1,3-oxazepine-4,7-dione (AMQ 1-5 ) were prioritized for actual synthesis and pharmacological screening for NMDA receptor antagonistic activity. Method: The prioritized molecules were synthesized and characterized by melting point, IR, 1 H-NMR, TLC and elemental analysis. AOT was performed to determine LD 50 of prioritized molecules, further compounds were evaluated for their in vivo antagonistic activity on NMDA induced convulsions in mice. Result: Prioritized molecules AMQ 1-5 exhibited potent antagonistic activity on NMDA receptor. Conclusion: The compound of series AMQ 1 and AMQ 5 were showed significant activity compared to standard memantine used in the assay.
Background: N-methyl-D-Aspartate (NMDA) receptor plays a main role in eliptogenisis and its inhibition has therapeutic significance in development of anticonvulsants. Prioritized quinazolinone molecules were synthesized, evaluated in vivo by AOT and then for anticonvulsant activity in NMDA induced convulsion model. Method: In silico Screening of prioritized molecule was done by biological activity predictions, partition coefficient predictions (Log P), molecular docking on NMDA receptors, in silico ADME predictions using PASS server and mol inspiration software, V Life MDS 4.3 software and Pre ADMET server respectively. This gave biological activity (BA) score for anticonvulsant activity and predicted Log P values (p Log P). The standard Log P required for anticonvulsant activities being more than 2.00, therefore molecules were also prioritized based on this p Log P criteria. Docking showed results of antagonism in silico as compared with Memnatine and molecules were prioritized for synthesis based on this criteria. Result: Quinazolinone molecules were prioritized based upon docking score, ADME and BA score, synthesized and pharmacologically screened for anticonvulsant activity. Conclusion: SMMB 1 , SMMB 2 , SMMB 3 showed the prominent anticonvulsant activity as compared with memantine used as standard for in vivo anticonvulsant activity. The compounds can serve as anticonvulsant Leads through NMDA antagonism.
Objective: The main objective of the present study was to evolve a novel pharmacophore of methaniminium derivatives as factor Xa inhibitors by developing best 2D and 3D QSAR models. The models were developed for amino (3-((3, 5-difluoro-4-methyl-6-phenoxypyridine-2-yl) oxy) phenyl) methaniminium derivatives as factor Xa inhibitors. Methods: With the help of Marvin application, 2D structures of thirty compounds of methaniminium derivatives were drawn and consequently converted to 3D structures. 2D QSAR using multiple linear regression (MLR) analysis and PLS regression method was performed with the help of molecular design suite VLife MDS 4.3.3. 3D QSAR analysis was carried out using k-Nearest Neighbour Molecular Field Analysis (k-NN-MFA). Results: The most significant 2D models of methaniminium derivatives calculated squared correlation coefficient value 0.8002 using multiple linear regression (MLR) analysis. Partial Least Square (PLS) regression method was also employed. The results of both the methods were compared. In 2D QSAR model, T_C_O_5, T_2_O_2, s log p, T_2_O_1 and T_2_O_6 descriptors were found significant. The best 3D QSAR model with k-Nearest Neighbour Molecular Field Analysis have predicted q2 value 0.8790, q2_se value 0.0794, pred r2 value 0.9340 and pred_r2 se value 0.0540. The stepwise regression method was employed for anticipating the inhibitory activity of this class of compound. The 3D model demonstrated that hydrophobic, electrostatic and steric descriptors exhibit a crucial role in determining the inhibitory activity of this class of compounds. Conclusion: The developed 2D and 3D QSAR models have shown good r2 and q2 values of 0.8002 and 0.8790 respectively. There is high agreement in inhibitory properties of experimental and predicted values, which suggests that derived QSAR models have good predicting properties. The contour plots of 3D QSAR (k-NN-MFA) method furnish additional information on the relationship between the structure of the compound and their inhibitory activities which can be employed to construct newer potent factor Xa inhibitors.
Neem () belonging to Maliaceae family is very important medicinal plant. Neem is used different medicinal system; Ayurveda, Unani, Homeopathic medicines against various diseases. Each part of neem tree which has some medical property which act on various diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.