Table 1 - uploaded by David J Triggle
Content may be subject to copyright.
Source publication
The 1,4-dihydropyridine nifedipine is a prototypical example of the group of calcium channel blockers that also includes a number of second and third generation agents. These drugs enjoy substantial therapeutic prominence for their cardiovascular actions, including hypertension and angina. These actions are exerted at a specific member of the volta...
Context in source publication
Context 1
... L-type class of voltage-gated calcium channel that is of particular, although not exclusive, functional significance in the cardiovascular system is but one subtype of a large class of voltage-gated calcium channels [designated according to functional and pharmacological properties as L, T, N, P/Q and R; Table 1], and this class is itself a subclass of a "super family" of voltage-gated calcium, potassium and sodium channels that share significant structural and functional homology [8][9][10][11] Table 3]. These differences likely relate to sequence differences that produce both different 1,4-dihydropyridine receptor recognition characteristics and different voltage-dependent interactions with the resting, open and inactivated channel states [13]. ...
Citations
... Several representatives (for example, comp.1; Figure 1) appeared to be more active for DNA delivery than commercially available cationic lipid DOTAP (N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethyl ammonium methylsulfate) and polymer PEI 25 (polyethyleneimine of 25 kDa) and have potential for use as transmembrane delivery systems [16,17]. The mentioned amphiphiles contain 1,4-DHP group as an active linker and, as stated by Triggle [18], are an intrinsic structural part of many pharmacologically active compounds and drugs. The first metabolic step of 1,4-DHPs is their oxidation to the pyridines. ...
Liposomes and other nanoparticles have been widely studied as innovative nanomaterials because of their unique properties. Pyridinium salts, on the basis of 1,4-dihydropyridine (1,4-DHP) core, have gained significant attention due to their self-assembling properties and DNA delivery activity. This study aimed to synthesize and characterize original N-benzyl substituted 1,4-dihydropyridines and evaluate the influence on structure modifications on compound physicochemical and self-assembling properties. Studies of monolayers composed of 1,4-DHP amphiphiles revealed that the mean molecular areas values were dependent on the compound structure. Therefore, the introduction of N-benzyl substituent to the 1,4-DHP ring enlarged the mean molecular area by almost half. All nanoparticle samples obtained by ethanol injection method possessed positive surface charge and average diameter of 395–2570 nm. The structure of the cationic head-group affects the size of the formed nanoparticles. The diameter of lipoplexes formed by 1,4-DHP amphiphiles and mRNA at nitrogen/phosphate (N/P) charge ratios of 1, 2, and 5 were in the range of 139–2959 nm and were related to the structure of compound and N/P charge ratio. The preliminary results indicated that more prospective combination are the lipoplexes formed by pyridinium moieties containing N-unsubstituted 1,4-DHP amphiphile 1 and pyridinium or substituted pyridinium moieties containing N-benzyl 1,4-DHP amphiphiles 5a–c at N/P charge ratio of 5, which would be good candidates for potential application in gene therapy.
... Among the derivatives of the DHP, 1,4 dihydropyridines (1,4-DHP), has been considered as an important structural scaffold for the treatment of numerous diseases, including T2DM [11]. The compound has been recognized as privileged structure by virtue of its ability to interact with different receptors [12], and most importantly, the possible anti-diabetic efficacy of the compound against α-glucosidase and α-amylase has been documented [13]. Based on the aforementioned anti-diabetic effect of the compounds, it will be appealing to subject the compounds to quantitative structure activity relationship (QSAR) analysis in order to find compounds with enhanced anti-diabetic activities. ...
Quantitative Structure Activity Relationship (QSAR) was employed to predict the inhibitory activities of some series of 1,4–dihydropyridines derivatives as potent C-terminal human intestinal maltase-glucoamylase inhibitor (MGAM-C). The Density Functional Theory utilizing B3LYP/6-31G* as the basis set was employed to optimize the chemical structure of 1,4–dihydropyridines derivatives. four models were generated using Genetic Function Approximation with model three having internal validation parameters of R ²(trng set) = 0.899, R ²adj = 0.869, Q ²cv = 0.769, LOF = 0.0129 selected as the best since it has the highest external validation parameter of R ²(test set) = 0.885. Five potent compounds designed using the ligand-based approach were found to be more enhanced than the template. furthermore, binding interactions of the designed compounds within the active site of (MGAM-C) showed a fascinating MolDock scores with good pharmacokinetic profiles. This study, provide a useful information for the design of new α-glucosidase inhibitors.
... Calcium channel blockers, cardiovascular, antihypertensive, antitumor, anti-inflammatory, analgesic, neuroprotectant, platelet antiaggregator, anti-ischemic, anti-Alzheimer, antimicrobial, and insecticidal are some of the biological functions of 1,4-DHP structures which are shown in Figure 1 [24][25][26][27][28][29][30]. ...
The synthesis of biologically active 1,4-dihyripyridine derivatives using a Calotropis gigantea leaf powder and ZnO NPs used as catalyst under solvent-free conditions at room temperature via grinding method has been established in a single-stage, mild, and environmentally friendly green process. The procedure is fast and effective and produces high yields. Three cancer cell lines were used to assess the cytotoxic activity of 1,4-dihyropyridine derivatives. The cytotoxicity of 1,4-dihyropyridine compound 1f (HepG2, LC50-0.50 μM, MCF-7, LC50-0.64 μM, and HeLa, LC50-0.52 μM) was found to be highly active. The synthesized derivatives demonstrated their safety by causing substantially less cytotoxicity in normal cell lines HEK-293, LO2, and MRC5 with IC 50 > 100 g/mL. As a result, compound 1f could serve as a high-impact molecule for the production of anticancer drugs in the future.
... 1,4-Dihydropyridines (1,4-DHP) belong to a class of six-membered nitrogen-containing heterocycles [1]. Among the family of dihydropyridines, most notable is Hantzsch type 1,4-DHP, which is regarded as a crucial scaffold that exists across a range of calcium channel antagonists that are widely used for the treatment of hypertension, angina pectoris, cardiac arrhythmias and other disorders [2][3][4]. Functionalisation of the 1,4-DHPs is a powerful tool for the construction of pharmacologically and biologically important compounds [5,6]. Thus, polyfunctional pyridinium amphiphiles on a base of 1,4-DHP were found to be active for DNA delivery. ...
In the present work, construction of double-charged cationic amphiphilic 1,1′-{[3,5-bis(dodecyl¬oxy-carbonyl)-4-(thiophen-3-yl)-1,4-dihydropyridine-2,6-diyl]bis-(methylene)}bis(pyridin-1-ium) dibromide (7) was performed in four steps. Dodecyl 3-oxobutanoate (1) was condensed with thiophene-3-carbaldehyde (2) which was necessary for Hantzsch cyclisation dodecyl (E/Z)-3-oxo-2-(thiophen-3-ylmethylene)butanoate (3). Two-component Hantzsch type cyclisation of dodecyl (E/Z)-3-aminobut-2-enoate (4) and dodecyl (E/Z)-3-oxo-2-(thiophen-3-ylmethylene)butanoate (3) gave 3,5-bis(dodecyloxycarbonyl)-2,6-dimethyl-4-(thiophen-3-yl)-1,4-dihydropyridine (5). Bromination of compound 5 followed by nucleophilic substitution of bromine with pyridine gave the desired cationic amphiphilic 1,4-dihydropyridine 7. The obtained target compound 7 and new intermediates 3, 5 and 6 were fully characterised by IR, UV, 1H NMR, 13C NMR, HRMS or microanalysis. Characterisation of nanoparticles formed by the cationic 1,4-dihydropyridine 7 in an aqueous solution was performed by DLS measurements.
... Over recent years, the concept of privileged structures (cyclic molecular platforms of a common structure, which can be bound to different biological targets upon variation of the substituents) has been elaborated in the field of development of novel biologically active molecules. 1,4-Dihydropyridines are among the privileged structures [24][25][26][27]. It is known that 1,4-dihydropyridines exhibit a wide range of practically important properties including cardioprotective, antihypertensive, antiinflammatory, analgesic, neuroprotective, and antithrombotic effects; SYNTHESIS, STRUCTURE, AND ANALGESIC ACTIVITY many derivatives of 1,4-dihydropyridine possess antimicrobial and insecticide action (see reviews [28][29][30][31][32][33][34][35]). ...
A series of new hybrid molecules containing fragments of anestesin and4-(2-furyl)-1,4-dihydronicotinonitrile have been obtained starting fromdiketene, ethyl 4-aminobenzoate, cyanothioacetamide, and furfural. The obtainedcompounds have been investigated for the analgesic activity in vivo (rats) in the orofacial trigeminal pain andacetic acid induced writhing tests. The compounds exhibiting analgesic effectsuperior to that of the reference drug (metamizole sodium) have been revealed.Molecular docking has been performed for the considered compounds with respectto a wide range of protein targets, including cyclooxygenases COX-1 andCOX-2.
... 1,4-Dihydropyridines, usually easile available through Hantzsch synthesis, are known for a long time as compounds of practical interest, primarily as cardioprotectors, HIV-1 protease inhibitors and calcium channel blockers (for reviews see [1][2][3][4][5][6][7]). Much less is known about sulfur-containing 1,4dihydropyridine-3-carboxamides which are expected to have a biological activity. ...
New triethylammonium 6-amino-4-aryl-3-carbamoyl-5-cyano-1,4-dihydropyridine-2-thiolates were prepared in good yields by the ternary condensation of malononitrile, aldehydes and monothiomalonamide in the presence of Et3N. The thiolates underwent S-alkylation under mild conditions to produce new 1,4-dihydronicotinamides. Molecular docking studies were carried out in order to explore the interaction mechanism and to investigate suitable binding modes of the new compounds on the calcium channel proteins. Some of the compounds in the in silico experiments were found to be more potent as calcium channel blockers than the reference drug, Nifedipine.
... Owing to their diversity in structural and medicinal applications, the 1,4-DHPs scaffold has been categorized as one of the privileged structures [1]. The reviewed biological importance of 1,4-DHPs include -calcium channel blockers, cardiovascular, anti-hypertensive, antitumor, anti-inflammatory, analgesic, neuroprotectant, platelet anti-aggregator, anti-ischemic, anti-alzheimer, anti-microbial and insecticidal etc. [1][2][3][4][5][6]. The noticeable drug candidates in this class have been shown in Fig. 1, Viz. are Nifedipine 1, Felodipine 2 and Amlodipine 3 etc. ...
The present work describes the design of 1,4-dihydropyridines (1,4-DHPs) with diverse variations in structural and functional groups. The physico-chemical properties and drug-like molecule nature evaluations were carried out using SWISSADME. A simple, economical, eco-friendly, water-mediated and Para-Toluene sulfonic acid catalysed multicomponent and one-pot synthetic method from nitroketene N, S- acetals (NMSM) and corresponding aldehydes has been developed. All compounds (6a-u and 13a-h) were subjected to in vitro assays against two important human cancer cell lines Viz. are Laryngeal carcinoma (Hep2) and Lung adenocarcinoma (A549) cells. The reduction level of DPPH (%) used to evaluate the anti-oxidant properties. The 1,4-DHP derivatives, 6o, 6u and 6l displayed the potent anti-cancer activity with IC50 value of 10 µM, 14 µM and 10 µM against the Hep2 and 8 µM, 9 µM and 50 µM against the A549 cells. Similarly, the anti-oxidant properties of 6o, 6l and 6u at a standard concentration of 50µg, are found to be 70.12%, 63.90% and 59.57% respectively favours the 1,4-DHP derivatives dual activity potentials. The compounds, 6o and 6l found to be equivalent with standard drug, Doxorubicin.
... belong to the most beneficial scaffolds with unprecedented biological properties that are investigated by pharmaceutical research providing medicines for the treatment of various diseases [1,2]. It is worth underlining that, according to Triggle, 1,4-DHP is a privileged structure that can interact at diverse receptors and ion channels and receptors of the G-protein class, when scaffold is properly substituted [3]. 4-Aryl-1,4-DHP derivatives are among the most active calcium antagonists [4]. ...
The purpose of this review is to highlight recent developments in the synthesis of chiral 1,4-dihydropyridines and their fused analogues. 1,4-Dihydropyridines are among the most active calcium antagonists that are used for the treatment of hypertension. Enantiomers of unsymmetrical 1,4-dihydropyridines often show different biological activities and may have even an opposite action profile. Hantzsch synthesis usually produces racemic mixtures of unsymmetrical 1,4-dihydropyridines. Therefore, the development of stereoselective synthesis of 1,4-dihydropyridines is one of the priorities of medicinal chemistry. Over the years, numerous methodologies have been developed for the production of enantiopure 1,4-dihydropyridines, such as stereoselective synthesis using chiral auxiliaries and chiral cyclocondensation partners, chromatographical methods, resolution of diastereomeric 1,4-dihydropyridine salts, enzyme catalysed kinetic resolution, or asymmetrisation of ester groups of 1,4-dihydropyridines. These approaches have been studied in detail and are relatively well established. The catalytic asymmetric approach holds the greatest promise in delivering the most practical and widely applicable methods. Substantial progress has been made toward the development of enantioselective organocatalytic methods for the construction of the chiral dihydropyridines. However, most of them do not provide a convenient way to pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates. Organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes also has great promise in the synthesis of pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates.
... Nifedipine is a dihydropyridine derivative, which exhibits antagonist effects on calcium channels. Dihydropyridines are widely used as arterialspecific vasodilators of peripheral resistance arteries that block calcium influx into arterial-wall smooth muscle and cause generalized vasodilation (Weiner, 1988;Triggle, 2003;Safak and Simsek, 2006). Oral nifedipine formulations have been investigated as a treatment for diabetic ulcers, peripheral vascular diseases (Rirash et al., 2017), wound healing and hypertrophic scars (Yamamoto et al., 2010;Santis et al., 2013), with moderate evidence of effectiveness. ...
Frostbite is a cold-related injury with a growing incidence among healthy subjects. Sequelae after frostbite are frequent and vary among individuals. Here, we studied the thermal response in the digits of hands and feet of five subjects who had recovered from previous frostbite, except for their lasting sequelae. We considered three different conditions: digits unaffected by frostbite nor sequelae (healthy), those affected but which did not suffer amputation (frostbitten without amputation), and the remainder/stumps of digits that underwent partial amputation (frostbitten with amputation). Three consecutive immersions in cold water (8°C; 3 min) interspersed by 1 minute of thermal recovery were performed. After 30 min, a topical 10% nifedipine preparation was applied to hands and feet, and the same cold exposure protocol to evaluate its effect was followed. In basal condition and immediately after each immersion, the temperature of individual digits was assessed using thermography. We observed different thermal responses among the different digits of hands and feet, even without the nifedipine treatment. Nifedipine had a cooling effect on healthy and post-amputated tissue without thermal stress. In cold conditions, topic nifedipine application improved the cold response in healthy fingers but had a negative effect on those from which parts had been amputated. The topical nifedipine had detrimental effects on toes in all conditions. Topical nifedipine can help to the preservation of healthy fingers exposed to cold, with adequate thermal insulation; but it is necessary to remark its potentially harmful effects on previously frostbitten tissue. Because of the differences observed on individual regional response to cold, thermography can be a useful tool in the frostbite prevention for subjects habitually exposed to cold environment.
... The 1,4-dihydropyridines (DHPs) are a class of calcium channel blockers (CCBs) that are widely used to treat cardiovascular disorders, including hypertension and angina [1]. By binding to the external, lipid-facing surface of the voltage-dependent Ca 2+ channel, dihydropyridines allosterically induce an asymmetric conformation of the channel, leading to the channel pore blocked by partially dehydrated Ca 2+ [2]. ...
