INTRODUCTION:

Hypertension, characterized by elevated blood pressure levels¹, affects a significant fraction of the global population and is a persistent and widespread global health concern. It poses a significant risk for strokes, heart attacks and kidney problems, and it affects the morbidity and death rates worldwide^2,3.

Dihydropyridine derivatives (DHPs) offer a variety of therapeutic effects and minimal toxicity, making them intriguing for the investigation of biological activity⁴.

1,4-Dihydropyridine(1,4-DHP) and its compounds are considered to be among the most valuable molecular frameworks in synthetic, organic, and medicinal chemistry. They are members of a potential family of nitrogen heterocycles⁵. The dihydropyridine's second and sixth alkyl groups are responsible for the activity's duration. Dihydropyridine's ester groups at positions three and five are essential for the migration of Calcium channel antagonists. The pharmacological action of the dihydropyridine is increased by substitution of an aromatic ring at position four⁴. The first 1,4-dihydropyridine synthesis was reported by Hantzsch, and it is currently considered to be one of the useful methods to synthesize 1,4-dihydropyridines efficiently in organic chemistry⁶.

Numerous pharmaceutical products with a 1,4-dihydropyridine moiety have been identified as L-type calcium channel blockers⁷. It is well known that calcium channel blockers cause vascular smooth muscle dilation by preventing calcium entrance⁸. According to studies, 1,4-DHP derivatives have a variety of uses in the management of cardiovascular illness, including effects as vasodilators⁹, cardiac depressants¹⁰ and antihypertensive¹¹. Additionally, they show significant antioxidant¹², analgesic¹³, anticonvulsant¹⁴, anti-inflammatory¹⁵, and antimicrobial¹⁶properties. These medications include felodipine, clevidipine, amlodipine, nifedipine, nilvadipine and pranidipine^17,18. The most effective class of antagonists consists of 1,4-dihydropyridine derivatives, the most common of which is nifedipine in modern medicine¹¹. The World Health Organization (WHO) lists nifedipine as one of the most effective and safe medications that are important. It is an L-type Calcium channel blocker that inhibits Ca²⁺influx and is suitable for all types of hypertension¹⁹.

Owing to its diverse range of pharmacological characteristics, a considerable amount of research has been done in recent years on the synthesis of these kind of compounds, making it a current and very relevant area of study. This paper outlines the synthesis of designed 1,4-dihydropyridine derivatives and their impact on lowering blood pressure when measured in rats using the tail cuff technique.

MATERIALS AND METHODS:

Materials:

The chemicals for the synthesis were acquired from Sigma Aldrich and Merck with high grade quality and used without purification. Thin layer chromatography was carried out to monitor the progress of the reaction on precoated silica gel plates (604GF254) and Ethyl acetate: n-Hexane (2:3) was used as solvent system. The products were characterized by IR spectral analysis using KBr pellet method, ¹H NMR using Bruker spectrospin-200 NMR spectrophotometer and CHCl₃ was the solvent used. Mass spectra was recorded on MAKE-WATERS SYNPT G2 QTOF.

Molecular Docking Studies:

Molecular docking for designed ten 1,4-dihydropyridine derivatives and the protein was performed using AutoDockTools 1.5.7 in order to determine the binding energies of the interaction between the 1,4-dihydropyridine derivatives and the protein (PDB ID: 3LV3). The Biovia Discovery Studio Visualizer was employed to visualize the protein-ligand complex. The protein data was sourced from the RCSB Protein Data Bank and processed with PyMOL²⁰. Ligands were drawn using ChemSketch²¹. The possible interaction of ligand with the selected protein and the results obtained were analysed and summarized in table 1.

Prediction of ADME properties:

1, 4-dihydropyridine derivatives was evaluated for ADME properties using Swiss ADME²². The corresponding outcomes are summarized in table 2.

Conventional approach for synthesizing 1,4-dihydropyridine (DHP) derivatives:

The mixture of aryl aldehyde, methyl-acetoacetate (11.3ml), ethyl-4-chloro aceto acetate (14.6ml) and ammonium hydroxide (1.8ml) is refluxed together in ethanol for about 16-18 hours²³. Different aryl aldehydes were used to synthesize 1,4- dihydropyridine derivatives (DHP-01: Salicyaldehyde(10.47ml), DHP-02: 3-Bromobenzaldehyde(18.5ml), DHP-03: Anisaldehyde (13.6ml), DHP-04: 4- Methyl benzaldehyde (12ml), DHP-05: 4- Chlorobenzaldehyde (14ml)). The obtained solid was filtered, washed with 1N HCl, 10% NaHCO₃ and 5% NaOH²⁴ and recrystallized using ethyl alcohol. TLC was used to monitor the reaction.

Pharmacological Evaluation:

All animals were procured from the CPCSCA-approved animal house of the Department of Pharmacology, Krupanidhi College of Pharmacy, Bengaluru (Reg. No: 378/01/ab/CPCSEA). Institutional Animal Ethics Committee Approval No. KCP/IAEC/ PCOL/59/2020 for experimental protocols.

Anti-hypertensive Activity:

A total of 48 Male albino Wistar rats, eight groups with six rats in each group were divided. Normal group rats were given distilled water as vehicle. Hypertension was induced (positive control) by oral administering the Wistar rats with N (ω)-nitro-L-arginine methyl ester (L-NAME) (80mg/kg body weight) dissolved in distillated water. To achieve the objective of the study the animals whose elevated systolic blood pressure was determined to be hypertensive (≥ 150mmHg) were employed. The standard group received L-NAME (80mg/kg/day) and Nifedipine (50mg/kg/day). Test groups were given a combination of L-NAME (80mg/kg/day) and one of the newly synthesized compounds (DHP-01 to DHP-05). The blood pressure was measured at Day 0, Day 14 and Day 28 using non invasive tail cuff method.

Tail cuff method:

In physiological research, the tail cuff method is a non-invasive way to take blood pressure readings in experimental animals, like rats and mice. In order to prevent variations in blood pressure, the ambient temperature in the experimental room is maintained. An inflatable cuff is placed around the animal's tail base. To measure blood flow and pressure variations in the tail artery, a pressure transducer is connected to the cuff. The baseline measurement was taken by inflating the cuff to a specified pressure, generally above the systolic level, which temporarily stops blood flow in the tail artery. The cuff was then slowly deflated, with pressure monitored until blood flow resumes, signaling the systolic pressure. This process was repeated to maintain consistency²⁵.

Statistical analysis:

GraphPad Prism version 5.01 was used to evaluate the experimental outcomes, and the data was represented as Mean±SEM. Dunnett's multiple comparison test was applied following one-way ANOVA to identify significant differences (P<0.05) between the groups.

Synthetic Scheme:

Figure 01: Scheme of the synthesis.

RESULTS AND DISCUSSION:

Table 01: Molecular docking results.

Sl. No

Compound code

Structure

Docking score

(Kcal/mol)

DHP-01

-7.11

DHP-02

-7.26

DHP-03

-6.46

DHP-04

-6.88

DHP-05

-6.62

DHP-06

-6.19

DHP-07

-6.13

DHP-08

-6.0

DHP-09

-5.27

DHP-10

-6.39

Figure 02: 2D Interaction of DHP - 02 binding with protein 3LV3.

Table 03: Drug& Rreceptor Binding Interactions.

Sl. No	Compound code	Receptor	Interacting residues
1	DHP-01	L-type receptor (PDB ID: 3LV3)	ILE 66, LYS 70, TYR 99, LEU 156
2	DHP-02	L-type receptor (PDB ID: 3LV3)	TRP 204, ARG 202, TRP 244, HIS 192
3	DHP-03	L-type receptor (PDB ID: 3LV3)	GLY 18, GLU 19, PRO 20, ARG 79, HIS 93, SER 13, GLY 91, PRO 15
4	DHP-04	L-type receptor (PDB ID: 3LV3)	THR 73, LYS 70, CYS 67, HIS 9, TYR 159, TYR 99, ILE 66, LEU 156, HIS 144
5	DHP-05	L-type receptor (PDB ID: 3LV3)	PRO 57, PRO 47, TRP 60, ARG 44, GLU 45

Figure 03: Systolic blood pressure in Wister rats.

Figure 04: Diastolic blood pressure in Wister rats.

Both the systolic and diastolic blood pressure values are presented as Mean±SEM (n=6). *P<0.05 showed a statistical significant difference compared to the positive control. **P<0.01 showed a statistical significant difference compared to the normal using One way ANOVA, Dunnett's multiple comparison test. *** P<0.001 showed statistical significant difference compared to the positive.

Docking studies:

The molecular docking was carried out for 10 designed derivatives of 1,4- dihydropyridine using the protein PDB ID:3LV3. Crystal structure of HLA-B*2705 in conjunction with a peptide that originates from the alpha1 subunit of the human voltage-dependent calcium channel was used for the study. The designed analogues (DHP 01-10) had docking score ranging from -5.27 to -7.26(Kcal/mol). Among the library of designed compounds, DHP-02 with the bromo group as the substituent at 2^nd position showed the highest docking score of -7.26Kcal/mol. Hantzsch synthesis was used to synthesize the best five 1,4-dihydropyridine derivatives based on the molecular docking results. ADMET properties of the synthesized compounds satisfied all the parameters of Lipinski’s rule of five. The compound’s antihypertensive activity was then evaluated after they were characterized using IR, ¹HNMR, and MASS.

Chemistry:

The synthesized compounds were characterized by Infrared Spectroscopy (IR), Proton Nucear Magnetic Resonance (¹HNMR) and Mass Spectrometry (MASS).

(a) 3-ethyl 5-methyl 2-(chloromethyl)-4-(2-hydroxyphenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (DHP-01)

Molecular Formula: C₁₈H₂₀ClNO₅. Molecular weight=365.81g/mol. IR Spectral data (in KBr) : 3340 cm^-1(N-H Str), 2980 cm^-1(O-H Str), 2889 cm^-1(C-H), 1713 cm^-1(C=O), 1608 cm^-1(c=c), 754 cm^-1 (Cl Halo). NMR Spectral data: 8.129 δ (s,1H,NH),6.551 δ(s,1H, CH), 2.557 δ (s,3H,CH₃), 1.207-1.278 δ (t, 3H, CH3), 4.19-4.226 (q, 2H,CH₂),2.280 δ (s,3H,CH3), 6.982-7.48 δ (m, 4H, Ar-H). MS Spectral data:365.91 M⁺.Melting point =182°C. Percentage yield = 45%

(b) 3-ethyl 5-methyl 4-(3-bromophenyl)-2-(chloromethyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (DHP-02)

Molecular Formula: C₁₈H₁₉BrNO₄. Molecular weight=428.70g/mol. IR Spectral data (in KBr) : 3476 cm^-1 (N-H Str), 3060 cm^-1 (C-H Str), 2977 cm^-1 (C-H Str methyl), 1886 cm^-1(C=O Str), 1692 cm^-1(C-H aromatic) 1498 cm^-1(C=C armoatic) 780 cm^-1(Cl halo). NMR Spectral data :7.26 δ (s,1H,NH), 6.639 δ (s,1H, CH), 2.565 δ (s, 3H,CH₃), 1.121-1.281 δ (t, 3H, CH₃), 4.123-4.2308 δ(q,2H,CH₂), 2.39 δ (s, 3H,CH₃), 7.253-7.412 δ (m, 5H,Ar-H). MS Spectral data: 428.80 M⁺.Melting point =186°C. Percentage yield = 60%

(c) 3-ethyl 5-methyl 2-(chloromethyl)-4-(4-methoxyphenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (DHP-03)

Molecular Formula: C₁₉H₂₂ClNO₅. Molecular weight=379.83g/mol. IR Spectral data (in KBr) : 3500 cm^-1(N-H Str ), 3068 cm^-1 (C-H), 2937 cm^-1 (C-H Str ), 1728 cm^-1(C=O), 1683 cm^-1 (C-H), 1460 cm^-1 (C-H ), 830 cm^-1(Cl halo). NMR Spectral data : 8.15 δ (s,1H,NH), 6.575 δ (s,1H CH),2.544 δ (s,3H CH₃),3.776 δ (s,3H,CH₃), 1.27-1.203 δ (t, 3H,CH₃), 4.107-4.214 δ (q, 2H,CH₂),2.399 δ (s,3H,CH₃), 6.785-7.398 δ (m,4H,Ar-H). MS spectral data:379.73 M⁺.Melting point =190°C. Percentage yield = 55%

(d) 3-ethyl 5-methyl 2-(chloromethyl)-6-methyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-dicarboxylate (DHP-04)

Molecular Formula: C₁₉H₂₂ClNO₄. Molecular weight=363.84g/mol .IR Spectral data (in KBr) : 3322 cm^-1(N-H Str), 3063 cm^-1 (O-H Str), 1626 cm^-1(C=C Str), 1205 cm^-1(C-O Str), 1029 cm^-1(C-N Str), 806 cm^-1 (C-Cl halo). NMR spectral data: 7.26 δ (s,NH,1H), 6.581 δ(s, 1H,CH), 2.553 δ (s, 3H,CH₃), 1.208-1.279 δ (t,3H,CH₃), 4.156-4.281 δ (q,2H,CH₂),2.408 δ (s, 3H,CH₃) 7.190-7.414 δ (m,4H,Ar-H). MS spectral data: 363.94 M⁺. Melting point =184°C. Percentage yield = 47%

(e) 3-ethyl 5-methyl 2-(chloromethyl)-4-(4-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (DHP-05):

Molecular Formula: C₁₈H₁₉Cl₂NO. Molecular weight=384.25g/mol. IR Spectral data (in KBr) : 3290 cm^-1 (N-H Str), 2981 cm^-1 ( C-H), 1904 cm^-1 (C-H aromatic ), 1682 cm^-1 (C=O Str),1306 cm^-1 (C-N Str). NMR spectral data : 7.38 δ (s, 1H,NH), 6.59 δ (s,1H,CH), 2.547 δ (s,3H,CH₃), 3.768 δ (s, 3H, CH₃), 1.222-1.257 δ (t,3H CH₃), 4.133-4.186 (q, 2H, CH₂), 2.401 δ (s,3H,CH₃), 6.799-7.277 δ (m, 4H, Ar-H). MS spectral data: 384.45 M⁺. Melting point =180ºC. Percentage yield = 58%

Pharmacological evaluation:

Based on antihypertensive activity performed using tail cuff method there was a considerable reduction in blood pressure between the groups given with the newly synthesized compounds (DHP-01 to DHP-05) and was compared with normal group, positive control and the standard group treated with nifedipine. It was confirmed that DHP-02 is highly significant as antihypertensive agent which can be screened clinically for antihypertensive activity.

CONCLUSION:

Novel 1,4- dihydropyridine derivatives were synthesized, characterized and evaluated for antihypertensive activity. Comparative research was done using Nifedipine as the standard drug to examine the efficacy of different structural modifications of 1,4-dihydropyridine derivatives.

The compounds had good binding affinity with L-type receptor of protein with PDB ID 3LV3. Binding energy was given best scoring results for five compounds (DHP-01 to DHP-05). DHP-02 had the highest binding energy. The synthesized compounds were obtained in the satisfactory yield. Newly synthesized 1,4-dihydropyridine derivatives can be further studied for antihypertensive activity.

ACKNOWLEDGEMENT:

We would like to thank the Principal and Management of Krupanidhi College of Pharmacy, Bangalore for their support and encouragement.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 18.03.2024 Revised on 24.07.2024

Accepted on 22.10.2024 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):2115-2120.

DOI: 10.52711/0974-360X.2025.00303

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Sl. No	Compound Code	Molecular Formula	Molecular weight	Log p	TPSA	Hydrogen Donors	Hydrogen Acceptors	Rotatable Bonds
1	DHP-01	C₁₈H₂₀ClNO₅	365.81g/mol	2.74	84.86	2	5	7
2	DHP-02	C₁₈H₁₉BrNO₄	428.70g/mol	3.64	64.63	1	4	7
3	DHP-03	C₁₉H₂₂ClNO₅	379.83g/mol	2.92	73.86	1	5	8
4	DHP-04	C₁₉H₂₂ClNO₄	363.84g/mol	3.32	64.63	1	4	7
5	DHP-05	C₁₈H₁₉Cl₂NO	384.25g/mol	3.48	64.63	1	4	7