1, 4-Dihydropyridines: A Class of Pharmacologically Important Molecules

Khedkar, Samrat A; Auti, Pratibha B.

doi:10.2174/1389557513666131119204126

Cited by 81 publications

(45 citation statements)

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“…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][8][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.…”

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confidence: 99%

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

El‐Moselhy

Sidhom

Esmat

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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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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confidence: 99%

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

El‐Moselhy

Sidhom

Esmat

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…1,4-DHPs possess several important pharmacological properties including calcium-channel-blocking, bronchodilator, anti-ischemic and antitumor as well as MDR reversal effects [10][11][12][13][14][15]. Several agents structurally related to 1,4-DHP derivatives have been reported as P-gp inhibitors [16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents

et al. 2020

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Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2 with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.

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“…The effects are expressed on smooth and cardiac muscle and even beyond the blood-brain barrier. In fact, some DHPs work better on certain types of vessels, for example on the coronary arteries or the cerebral vessels [5]. The striated muscles are free from these effects because the mechanism is a function of the calcium already present within the cells.…”

Section: Introductionmentioning

confidence: 99%

“…Currently, calcium antagonists used as antihypertensive agents are almost exclusively DHP compounds, while non-DHP drugs are mainly used as antiarrhythmics [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Photodegradation of 1, 4-Dihydropyridine Antihypertensive Drugs: An Updated Review

Luca

Ioele

Spatari

et al. 2018

Int J Pharm Pharm Sci

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ABSTRACT1, 4-dihydropyridine calcium channels blockers (DHPs) are the most commonly used antihypertensive drugs. Unfortunately, these compounds have a significant degradability to light. The oxidation to the pyridine derivative represents the first, and in many cases the only, step of the degradation mechanism. The photodegradation process causes the complete loss of pharmacological activity and may trigger the formation of single and superoxide oxygen species, potentially responsible for phototoxic reactions. Several analytical techniques have been proposed for DHP determination in the presence of their photoproducts. Nowadays, DHPs are all marketed in solid formulations, especially tablets, because photodegradation is particularly fast in solution. Various approaches aimed to protect molecular integrity and therapeutic activity of these drugs from the effects of light are currently studied. This review covers the studies over the last years about photodegradation of the DHPs and the approaches to obtain photostable formulations of these drugs.

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1, 4-Dihydropyridines: A Class of Pharmacologically Important Molecules

Cited by 81 publications

References 0 publications

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

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

5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents

Photodegradation of 1, 4-Dihydropyridine Antihypertensive Drugs: An Updated Review

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