Synthesis and molecular docking studies of 4H-chromene derivatives as a calcium channel blocking agent

Subject Areas : Medicinal Chemistry

somayeh makarem ¹ (Department of chemistry, Karaj branch, Islamic Azad University, Karaj, Iran.)
yalda kashkooli ² (1Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran)
Afshin Rajabi Khorrami ³ (Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran)
Shabnam nadjafi ⁴ (Assistant Professor of Pharmacology, Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran)

Received: 2024-03-02 Accepted : 2024-06-06 Published : 2024-06-11

Keywords: Electrosynthesis, Knoevenagel, Calcium channel blocking agents, Nimodipine, Molecular docking studies.,

Abstract :

Voltage-gated Ca2+ channels play a vital role in the transmission of electrical signals by temporarily increasing intracellular Ca2+ levels and exerting an action potential on the cell surface membrane. As a blocker of calcium channels, nimodipine specifically blocks L-type calcium channels, which are present in smooth muscle cells in blood vessels. By blocking these channels, nimodipine prevents calcium from entering the cells, resulting in relaxation and dilation of the blood vessels. In this way, several 4H-chromene derivatives were obtained through electro synthesis in propanol, using electrons as a catalyst to generate propanol anion as a base. This process involved obtaining malononitrile anion, which readily underwent Knovenagel condensation with aromatic aldehydes, followed by the reaction of the active methylene of dimedione with the electrophile C=C of the intermediate. Finally, the expected product was o−btained through cyclisation and tautomerization. The effect of current, solvent, and anode type were studied, and it was observed that the optimized current, solvent, and anode for the synthesis of nanoparticles of 4H-chromene were 50 mA/cm2, propanol, and a magnesium anode in an undivided cell at room temperature. The proposed method produces 4H-chromene directly from initial compounds in a mild and safe condition. All synthesized compounds were screened through molecular docking studies, which utilized the crystal structure of CavAb. Compound 8f exhibited the minimum binding energy and good affinity toward the active pocket of CavAb compared to nimodipine as a calcium channel blocking agent.

References:

1. Brahmachari G. Chapter 8 - Green Synthetic Approaches for Biologically Relevant 2-amino-4H-pyrans and 2-amino-4H-pyran-Annulated Heterocycles in Aqueous Media∗. In: Brahmachari G, editor. Green Synthetic Approaches for Biologically Relevant Heterocycles. Boston: Elsevier; 2015. p. 185-208.
2. Kathrotiya HG, Patel MP. Microwave-assisted synthesis of 3′-indolyl substituted 4H-chromenes catalyzed by DMAP and their antimicrobial activity. Medicinal Chemistry Research. 2012;21(11):3406-16.
3. Alvey L, Prado S, Saint-Joanis B, Michel S, Koch M, Cole ST, et al. Diversity-oriented synthesis of furo[3,2-f]chromanes with antimycobacterial activity. European Journal of Medicinal Chemistry. 2009;44(6):2497-505.
4. Kumar D, Reddy VB, Sharad S, Dube U, Kapur S. A facile one-pot green synthesis and antibacterial activity of 2-amino-4H-pyrans and 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromenes. European Journal of Medicinal Chemistry. 2009;44(9):3805-9.
5. Symeonidis T, Chamilos M, Hadjipavlou-Litina DJ, Kallitsakis M, Litinas KE. Synthesis of hydroxycoumarins and hydroxybenzo[f]- or [h]coumarins as lipid peroxidation inhibitors. Bioorganic & Medicinal Chemistry Letters. 2009;19(4):1139-42.
6. Narender T, Shweta, Gupta S. A convenient and biogenetic type synthesis of few naturally occurring chromeno dihydrochalcones and their in vitro antileishmanial activity. Bioorganic & Medicinal Chemistry Letters. 2004;14(15):3913-6.
7. Paliwal PK, Jetti SR, Jain S. Green approach towards the facile synthesis of dihydropyrano(c)chromene and pyrano[2,3-d]pyrimidine derivatives and their biological evaluation. Medicinal Chemistry Research. 2013;22(6):2984-90.
8. Cai SX, Drewe J, Kemnitzer W. Discovery of 4-aryl-4H-chromenes as potent apoptosis inducers using a cell- and caspase-based Anti-cancer Screening Apoptosis Program (ASAP): SAR studies and the identification of novel vascular disrupting agents. Anticancer Agents Med Chem. 2009;9(4):437-56.
9. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, et al. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci U S A. 2000;97(13):7124-9.
10. van Otterlo WAL, Ngidi EL, Kuzvidza S, Morgans GL, Moleele SS, de Koning CB. Ring-closing metathesis for the synthesis of 2H- and 4H-chromenes. Tetrahedron. 2005;61(42):9996-10006.
11. Hufford CD, Oguntimein BO, Van Engen D, Muthard D, Clardy J. Vafzelin and uvafzelin, novel constituents of Uvaria afzelii. Journal of the American Chemical Society. 1980;102(24):7365-7.
12. Panda D, Singh JP, Wilson L. Suppression of microtubule dynamics by LY290181: A potential mechanism for its antiproliferative action. Journal of Biological Chemistry. 1997;272(12):7681-7.
13. Dan LW, Dulal P, Todd RW, Leslie W, Mary Ann J, Jai Pal S. Inhibition of Mitosis and Microtubule Function through Direct Tubulin Binding by a Novel Antiproliferative Naphthopyran LY290181. Molecular Pharmacology. 1997;52(3):437.
14. Smith CW, Bailey JM, Billingham MEJ, Chandrasekhar S, Dell CP, Harvey AK, et al. The anti-rheumatic potential of a series of 2,4-di-substituted-4H-naphtho[1,2-b]pyran-3-carbonitriles. Bioorganic & Medicinal Chemistry Letters. 1995;5(23):2783-8.
15. Kheirollahi A, Pordeli M, Safavi M, Mashkouri S, Naimi-Jamal MR, Ardestani SK. Cytotoxic and apoptotic effects of synthetic benzochromene derivatives on human cancer cell lines. Naunyn-Schmiedeberg's Archives of Pharmacology. 2014;387(12):1199-208.
16. El-Agrody AM, El-Mawgoud HKA, Fouda AM, Khattab ESAEH. Synthesis, in-vitro cytotoxicity of 4H-benzo[h]chromene derivatives and structure–activity relationships of 4-aryl group and 3-, 7-positions. Chemical Papers. 2016;70(9):1279-92.
17. El-Agrody AM, Fouda AM, Khattab ESAEH. Synthesis, antitumor activity of 2-amino-4H-benzo[h]chromene derivatives, and structure–activity relationships of the 3- and 4-positions. Medicinal Chemistry Research. 2013;22(12):6105-20.
18. El-Agrody AM, Fouda AM, Khattab ESAEH. Halogenated 2-amino-4H-benzo[h]chromene derivatives as antitumor agents and the relationship between lipophilicity and antitumor activity. Medicinal Chemistry Research. 2017;26(4):691-700.
19. El-Agrody AM, Halawa AH, Fouda AM, Al-Dies A-AM. The anti-proliferative activity of novel 4H-benzo[h]chromenes, 7H-benzo[h]-chromeno[2,3-d]pyrimidines and the structure–activity relationships of the 2-, 3-positions and fused rings at the 2, 3-positions. Journal of Saudi Chemical Society. 2017;21(1):82-90.
20. Halawa AH, Fouda DA, Al-dies A-a, El-Agrody A. Synthesis, biological evaluation and molecular docking studies of 4Hbenzo[ h]chromenes, 7H-benzo[h]chromeno[2,3-d]pyrimidines as Antitumor Agents. 2016;13:77-88.
21. El-Agrody AM, Fouda AM, Al-Dies A-AM. Studies on the synthesis, in vitro antitumor activity of 4H-benzo[h]chromene, 7H-benzo[h]chromene[2,3-d]pyrimidine derivatives and structure–activity relationships of the 2-,3- and 2,3-positions. Medicinal Chemistry Research. 2014;23(6):3187-99.
22. Abdelrazek FM, Metz P, Farrag EK. Synthesis and molluscicidal activity of 5-oxo-5,6,7,8-tetrahydro-4H-chromene derivatives. Arch Pharm (Weinheim). 2004;337(9):482-5.
23. Saddala MS, Kandimalla R, Adi PJ, Bhashyam SS, Asupatri UR. Novel 1, 4-dihydropyridines for L-typecalcium channel as antagonists for cadmium toxicity. Scientific Reports. 2017;7(1):45211.
24. Wulff H, Christophersen P. Recent developments in ion channel pharmacology. Channels (Austin, Tex). 2015;9(6):335.
25. Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011;3(8):a003947.
26.William AC, Teresa MS. Structural Basis for Pharmacology of Voltage-Gated Sodium and Calcium Channels. Molecular Pharmacology. 2015;88(1):141.
27. Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Chou SN, et al. Cerebral Arterial Spasm – A Controlled Trial of Nimodipine in Patients with Subarachnoid Hemorrhage. New England Journal of Medicine. 1983;308(11):619-24.
28. Makarem S, Fakhari AR, Mohammadi AA. Electro-organic synthesis of nanosized particles of 3-hydroxy-3-(1H-indol-3-yl)indolin-2-one derivatives. Monatshefte für Chemie - Chemical Monthly. 2012;143(8):1157-60.
29. Makarem S, Fakhari AR, Mohammadi AA. Electro-organic synthesis of nanosized particles of 2-amino-pyranes. Industrial & engineering chemistry research. 2012;51(5):2200-4.
30. Darvish ZM, Mirza B, Makarem S. Electrocatalytic multicomponent reaction for synthesis of nanoparticles of spirooxindole derivatives from isatins, malononitrile, and dimedone. Journal of Heterocyclic Chemistry. 2017;54(3):1763-6.
31. Makarem S, Fakhari AR, Mohammadi AA. Electro-organic synthesis: an efficient method for the preparation of nanosized particles of phthalazine derivatives via one-pot multicomponent reactions. Analytical and Bioanalytical Chemistry Research. 2015;2(2):85-9.
32. Makarem S, Amiri Notash N. Synthesis and Molecular Docking Studies of 2-arylideneindan-1, 3-diones Derivatives as an Inhibitor of 17β-hydroxysteroid Dehydrogenase Type 1. Journal of Applied Chemical Research. 2020;14(1):32-43.
33. Asghariganjeh MR, Mohammadi AA, Tahanpesar E, Rayatzadeh A, Makarem S. Synthesis and Molecular Docking studies of Some Tetrahydroimidazo [1, 2-a] pyridine Derivatives as Potent α-Glucosidase Inhibitors. Journal of Applied Chemical Research. 2021;15(1):24-35.
34. Tang L, Gamal El-Din TM, Swanson TM, Pryde DC, Scheuer T, Zheng N, et al. Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature. 2016;537(7618):117-21.
35. Guo R-Y, An Z-M, Mo L-P, Wang R-Z, Liu H-X, Wang S-X, et al. Meglumine: A Novel and Efficient Catalyst for One-Pot, Three-Component Combinatorial Synthesis of Functionalized 2-Amino-4H-pyrans. ACS Combinatorial Science. 2013;15(11):557-63.
36. Khazaei A, Gholami F, Khakyzadeh V, Moosavi-Zare AR, Afsar J. Magnetic core–shell titanium dioxide nanoparticles as an efficient catalyst for domino Knoevenagel–Michael-cyclocondensation reaction of malononitrile, various aldehydes and dimedone. RSC Advances. 2015;5(19):14305-10.
37. Esmaeilpour M, Javidi J, Dehghani F, Dodeji FN. A green one-pot three-component synthesis of tetrahydrobenzo [b] pyran and 3, 4-dihydropyrano [c] chromene derivatives using a Fe3O4@ SiO 2–imid–PMA n magnetic nanocatalyst under ultrasonic irradiation or reflux conditions. RSC Advances. 2015;5(34):26625-33.