1,4-Dihydropyridine: synthetic advances, medicinal and insecticidal properties

Abstract

1,4-Dihydropyridine (1,4-DHP) is one of the foremost notable organic scaffolds with diverse pharmaceutical applications. This study will highlight recent accomplishments in the construction of 1,4-DHP with structural and functional modifications using multi-component one-pot and green synthetic methodologies. The various intrinsic therapeutic applications, ranging from calcium channel blocker, anti-oxidative, anticancer, anti-inflammatory, anti-microbial, anti-hypertensive, anti-diabetic, anticoagulants, anti-cholinesterase, neuro-protective, and other miscellaneous activities, have been summarized with a focus on their structure-activity relationship (SAR) investigations. In addition, the insecticidal properties have been collated and discussed. Researchers in the fields of medicinal chemistry and drug development will find the summarized conclusions of this study incredibly informative, instructional, and valuable.

Scheme 1. The possible reductions of pyridine and generation of the 1,2-DHP (1a) and 1,4-DHP (1b) scaffolds.

Fig. 1. The number of publications published on 1,4-DHP scaffolds since 1969 (https://pubmed.ncbi.nlm.nih.gov/?term=1%2C4-dihydropyridine).

Scheme 2. The Hantzsch synthetic method, a classical 1,4-DHP synthesis.

Scheme 3. Hyphothesis for preparation of chiral Hantzsch type 1,4-DHPs.

Scheme 4. Nucleophilic allylation of azinium ions.

Scheme 5. Synthesis of 1,4-DHP using the fluorescent probe.

Scheme 6. Synthesis of amlodipine 1,4-DHP derivatives.

Scheme 7. Synthesis of 1,4-DHPs based triazole derivatives.

Scheme 8. Synthesis of dicarboxlyic-1,4-DHP derivatives.

Scheme 9. Synthesis of symmetrical 1,4-DHPs.

Scheme 10. Synthesis of 1,4-DHPs using NMO.

Scheme 11. Synthesis of 1,4-DHPs by MnFe₂0₄ nanoparticles.

Scheme 12. Synthesis of 1,4-DHPs adorned with gem-difluoromethylene motif.

Scheme 13. Synthesis of 1,4-DHPs using neat conditions.

Scheme 14. Synthesis of 1,4-DHPs using SBC conditions.

Scheme 15. Synthesis of 1,4-DHP using microwave conditions.

Scheme 16. Synthesis of 1,4-DHP using microwave in water conditions.

Scheme 17. Synthesis of 1,4-dihydropyridine in visible light.

Scheme 18. Glycine nitrate ionic liquid catalyzed synthesis of 1,4-dihydropyridines.

Scheme 19. Yb(OTf)₃ Lewis acid-catalyzed synthesis of 1,4-DHPs.

Scheme 20. The cellulose sulphuric acid medicated synthesis of C5-unsubstituted 1,4-DHPs.

Scheme 21. Palladium-assisted synthesis of 1,4-DHPs.

Scheme 22. Synthesis of unsymmetrical 4-arylacridinediones under neat condition.

Scheme 23. Three-component reaction for the generation of 1,4-DHPs.

Scheme 24. Et₃N catalysed synthesis of polysubstituted 1,4-DHPs.

Scheme 25. TFA catalyzed synthesis of 1,4-DHPs.

Scheme 26. Synthesis of 3-cyano-5-nitro-substituted 1,4-DHPs.

Scheme 27. Synthesis of imidazo[1,2-a]thiochromeno[3,2-e]pyridine.

Scheme 28. Synthesis of 3,5-dinitrosubstituted 1,4-DHPs.

Scheme 29. HKUST-1 catalyzed synthesis of 1,4-DHPs under solvent-free conditions.

Scheme 30. Preparation of 1,4-DHPs in the presence of aminated MWCNTs.

Scheme 31. Synthesis of 1,4-DHP using CAN catalyst.

Scheme 32. Synthesis of 1,4-DHP under catalyst-free conditions.

Scheme 33. Synthesis of 1,4-DHP under piperazine catalyst.

Scheme 34. Synthesis of 1,4-DHP using piperazine (0.15 mmol) and TMSCl catalyst.

Scheme 35. Synthesis of 1,4-DHPs using Cu(OTf)₂ catalyst.

Scheme 36. Synthesis of 1,4-DHP using l-proline catalyst.

Scheme 37. Synthesis of 1,4-DHP using PTSA.

Scheme 38. Synthesis of 1,4-DHP using NH₄OAc.

Scheme 39. Synthesis of 1,4-DHP neat conditions.

Scheme 40. 1,4-DHPs Hantzsch synthesis and limitations.

Scheme 41. The pseudo three components for the synthesis of 1,4-DHP and plausible mechanism.

Fig. 2. Structure of NADH and NADPH.

Scheme 42. The antihypertensive activity of CD-349.

Scheme 43. Antihypertensive activity of nitroxyalkyl 1,4-DHP derivatives.

Scheme 44. Antihypertensive activity of 5-imidazolyl DHP derivatives.

Scheme 45. Antihypertensive acivity of 1,4-DHPs bearing 3-[4-(substituted amino)phenylalkyl]ester derivatives.

Scheme 46. Antihypertensive activity of 1,4-DHPs bearing 3-aminoethylester derivatives.

Scheme 47. Antihypertensive activity of 1,4-DHPs bearing nitroxy-alkoxycarbonyl derivatives.

Scheme 48. Antihypertensive activity of 1,4-DHPs bearing 2-methylthio-1-phenylamino-5-imidazolyl derivatives.

Fig. 3. SAR studies of antihypertensive acitivity of 1,4-DHPs.

Scheme 49. Cyclohexane ring fused 1,4-DHPs as potential calcium channel blockers.

Scheme 50. The condensed 1,4-DHP ring system act as potential calcium channel blockers.

Fig. 4. Structure of 1,4-DHP based channel blockers.

Scheme 51. 1,4-DHPs act as potential calcium channel blockers.

Scheme 52. The nitroimidazoly1-1,4-DHPs as potential calcium channel blockers.

Scheme 53. 1,4-DHPs cationic pyridine moiety act as calcium channel blockers.

Fig. 5. SAR studies of calcium channel blockers acitivity of 1,4-DHPs.

Fig. 6. SAR studies of nitro group containing 1,4-DHPs.

Scheme 54. The nitro substituted 1,4-DHPs as anticancer agents.

Scheme 55. The 1,4-DHPs-3,5-dicarbohydrazide derivatives as anticancer agents.

Scheme 56. The sulphoxide 1,4-DHPs as anticancer agents.

Scheme 57. The benzylpyridinium moiety 1,4-DHPs as antitcancer agents.

Scheme 58. The phenothiaziny1-1,4-DHPs-dicarboxamides as anticancer agents.

Scheme 59. The notrogen mustard pharmacophore hybride as anticancer agents.

Fig. 7. SAR studies of anti-cancer activity of 1,4-DHPs.

Scheme 60. The dihydrazine carbothioamides 1,4-DHPs as anti-inflammatory agents.

Scheme 61. The 4-(3-arylureido)pheny1-1,4-DHPs urea derivatives as anti-inflammatory agents.

Fig. 8. SAR studies of anti-inflammatory agents of 1,4-DHPs.

Scheme 62. The 1,2,3-triazoly1-1,4-DHPs hybrids as anti-microbial agents.

Scheme 63. The 3,5-diacety1-1,4-dihydro-2,4,6-trimethylpyridine as anti-microbial agents.

Scheme 64. The quinoline bearing 1,4-DHP derivatives as anti-microbial agents.

Scheme 65. The cationic peptidomimetics centred on a hydrophobic 1,4-DHP as anti-microbial agents.

Scheme 66. The carbamoyl 1,4-DHPs as anti-microbial agents.

Scheme 67. The triazole 1,4-DHPs as anti-microbial agents.

Fig. 9. SAR studies of anti-microbial agents of 1,4-DHPs.

Scheme 68. The chalcone-substituted 1,4-DHPs as anti-oxidant agents.

Scheme 69. The flavonil-1,4-DHPs as anti-oxidant agents.

Scheme 70. The N-aryl-1,4-DHPs as anti-oxidant agents.

Scheme 71. The long-chain fatty DHPs as anti-oxident agents.

Fig. 10. SAR studies of the antioxidant activity of 1,4-DHPs.

Scheme 72. The 4,6-diaryl-1,4-DHPs as neuroprotective agents.

Scheme 73. The thiadiazol sulfonyl anamide 1,4-DHPs as anticholinesterase agents.

Scheme 74. The thiosemicarbazide 1,4-DHPs as anticoagulant agents.

Scheme 75. The phenylthiadiazol-2amine 1,4-DHPs as anticoagulant agents.

Scheme 76. The triazol 1,4-DHP derivatives as antidiabetic agents.

Scheme 77. cis-Nitenpyram analogues containing 1,4-DHPs.

Scheme 78. Synthesis of neonicotinied insecticide analogue.

Scheme 79. Synthesis of 1,4-DHPs and cis-nitenpyram hybrid analogues.

Scheme 80. Synthesis and insecticidal activities.

Scheme 81. Synthesis of insecticides.

Scheme 82. Synthesis of insecticides.

Scheme 83. Synthesis of insecticides.

Scheme 84. Synthesis of insecticidal neonicotinoid and 1,4-DHPs hybrids.

Scheme 85. Synthesis of insecticides.

Scheme 86. Synthesis of neonicotinoids insecticides with trifluoromethyl group.

Scheme 87. Synthesis of neonicotinoids insecticides with ester group.

Fig. 11. SAR studies of insecticidal activities.

Parthiban A.

Parameshwar Makam