TY - JOUR

T1 - Multi-step synthesis of novel 2-methyl-3-carboxamide-4-quinolones and an enhanced sampling simulation method to identify potentiators for cystic fibrosis

AU - Sharma, Bhanu

AU - Muthipeedika, Nibin joy

AU - Bhattacherjee, Dhananjay

AU - Zyryanov, Grigory

AU - Purohit, Rituraj

N1 - Текст о финансировании #1 We gratefully acknowledge to the Director, CSIR -Institute of Himalayan Bioresource Technology, Palampur for providing the facilities to carry out this work. BS acknowledges the Department of Biotechnology, New Delhi, India for providing junior research fellowship File No: DBTHRDPMU/JRF/BET- 20/I/2020/AL/36. The CSIR support in the form of project MLP:0201 for bio-informatics studies is highly acknowledge. For G.V.Z. this work was financially supported by the Ministry of Science and Higher Education of the Russian Federation within the framework of the grant agreement as government subsidies from the Federal budget in accordance with paragraph 4 of article 78.1 of the Budget Code of the Russian Federation (Moscow, October 1, 2020, No. 075-15-2020-777). Текст о финансировании #2 We gratefully acknowledge to the Director, CSIR-Institute of Himalayan Bioresource Technology, Palampur for providing the facilities to carry out this work. BS acknowledges the Department of Biotechnology, New Delhi, India for providing junior research fellowship File No: DBTHRDPMU/JRF/BET- 20/I/2020/AL/36. The CSIR support in the form of project MLP:0201 for bio-informatics studies is highly acknowledge. For G.V.Z. this work was financially supported by the Ministry of Science and Higher Education of the Russian Federation within the framework of the grant agreement as government subsidies from the Federal budget in accordance with paragraph 4 of article 78.1 of the Budget Code of the Russian Federation (Moscow, October 1, 2020, No. 075-15-2020-777).

PY - 2023

Y1 - 2023

N2 - Cystic fibrosis (CF) is a life-threatening hereditary disease caused by mutations in the CF trans membrane conductance regulator (CFTR) gene. The commonly utilized medication for CF is a potentiator that restores CFTR function by stabilizing the channel in open conformation. A multistep synthesis method has been demonstrated here for synthesizing 2-methyl-3-carboxamide-4-quinolones having potential activities on CF. The synthesized molecules were obtained in quantitative yield and purified using recrystallization techniques without column purification. An extensive computational analysis was carried out to access the potential of 2-methyl-3-carboxamide-4-quinolones as potentiators. The computational analysis using molecular docking, classical and membrane-embedded molecular dynamics simulations in different lipid environments, and MM-PBSA revealed that the molecule 4d formed a stable complex. The binding free energies from umbrella sampling simulations for standard molecules ivacaftor and GPLG1837 were −26.133 kJ/mol and −28.471 kJ/mol, respectively, while for 4d a lower free energy value was obtained (−37.852 kJ/mol), which further strengthened the candidature of 4d as a promising potentiator molecule. This research identified a hit molecule that could be utilized further in in-vitro and in-vivo studies to establish it as a potentiator against CF and also provided a suitable and efficient synthesis method for the pharmaceutical industries. © 2023 Elsevier Ltd.

AB - Cystic fibrosis (CF) is a life-threatening hereditary disease caused by mutations in the CF trans membrane conductance regulator (CFTR) gene. The commonly utilized medication for CF is a potentiator that restores CFTR function by stabilizing the channel in open conformation. A multistep synthesis method has been demonstrated here for synthesizing 2-methyl-3-carboxamide-4-quinolones having potential activities on CF. The synthesized molecules were obtained in quantitative yield and purified using recrystallization techniques without column purification. An extensive computational analysis was carried out to access the potential of 2-methyl-3-carboxamide-4-quinolones as potentiators. The computational analysis using molecular docking, classical and membrane-embedded molecular dynamics simulations in different lipid environments, and MM-PBSA revealed that the molecule 4d formed a stable complex. The binding free energies from umbrella sampling simulations for standard molecules ivacaftor and GPLG1837 were −26.133 kJ/mol and −28.471 kJ/mol, respectively, while for 4d a lower free energy value was obtained (−37.852 kJ/mol), which further strengthened the candidature of 4d as a promising potentiator molecule. This research identified a hit molecule that could be utilized further in in-vitro and in-vivo studies to establish it as a potentiator against CF and also provided a suitable and efficient synthesis method for the pharmaceutical industries. © 2023 Elsevier Ltd.

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U2 - 10.1016/j.mtchem.2023.101731

DO - 10.1016/j.mtchem.2023.101731

M3 - Article

VL - 33

JO - Materials Today Chemistry

JF - Materials Today Chemistry

SN - 2468-5194

M1 - 101731

ER -