Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

Abstract

Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC 50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3-and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr) 4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3-and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.Key words calcium channel; dihydropyridine; docking; synthesis; three-dimensional quantitative structureactivity relationship (3D-QSAR) Precise regulation of calcium homeostasis is crucial for many physiological functions.1) Divergent types of calcium channels and pumps can control the influx of calcium ions into cells.2,3) Consequently, targeting calcium channels is advantageously beneficial to yield useful drugs. Ca V 1.2 blockers can be roughly categorized into three different chemical classes: 1,4-dihydropyridine (DHP) derivatives, phenylalkylamine derivatives and benzothiazepine derivatives. Among them, DHP derivatives have the most significant pharmacological importance. For example, amlodipine is among the top-five best selling drugs in the treatment of cardiovascular diseases. Various modulators can potentiate or block calcium entry through L-type calcium channels. [4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, 7-9) antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.18) The twelve approved DHP calcium antagonists developed are vasodilators.19) Vasodilatation is due to the uncoupling of the contractile mechanism of vascular smooth muscle, which requires Ca 2+ . 20)Structure-activity relationship (SAR) of DHP 21) and the clinical usage of nifedipine have promoted us to synthesize two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking st...

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“…[373][374][375] The most common synthetic procedure to obtain pyridines is using the Hantzsch reaction. [376][377][378][379][380][381][382][383] The preparation of 1,4-dihydropyridines requires two equivalents of β-keto ester, an aldehyde and nitrogen donor. Sudalai and co-workers utilized dimethylmalonate 35 as the β-keto ester, 2-nitro-benzaldehyde 36 for the aldehyde and ammonium acetate as the nitrogen donor (Scheme 9).…”

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