The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design

Abstract

Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.

Keywords: bioactive compounds; current trend; nitrogen heterocycles; pharmaceuticals; substituent effect.

Figure 1

Distribution of N-heterocyclic drugs in the FDA database.

Figure 2

Substitution-type analysis of pyridine- (A) and dihydropyridine (B)-containing FDA-approved drugs.

Figure 3

Publications on pyridine- and dihydropyridine-containing compounds, 2010–2020 (source: Scopus and SciFinder).

Figure 4

Pyridine and dihydropyridine ring system in medicinally important natural products.

Figure 5

Effect of pyridine on key pharmacological parameters.

Figure 6

Some commercially available drugs containing the pyridine scaffold.

Figure 7

Some commercially available drugs containing the dihydropyridine scaffold.

Figure 8

FDA-approved vasodilators containing both pyridine and dihydropyridine scaffolds.

Figure 9

Substitution-pattern analysis in pyridine and dihydropyridine in FDA-approved drugs.

Figure 10

Dodecylpyridinium moiety containing dihydropyridines with potent calcium antagonism in the A7r5 cell line.

Figure 11

FDA-approved drugs containing pyridine or dihydropyridine scaffolds for the treatment of hypertension.

Figure 12

Highly potent calcium-channel antagonists.

Figure 13

Calcium-channel antagonists.

Figure 14

N-aryl-1,4-dihydropyridines containing thiosemicarbazone.

Figure 15

Cholesterol-lowering drugs in the statin class.

Figure 16

Antihyperlipidemic (benzoylphenyl)pyridine-3-carboxamide compounds.

Figure 17

Cholesterol-lowering compounds (18–22) containing dihydropyridine rings.

Figure 18

Pyridine-containing antibiotics approved by the FDA during the last decade.

Figure 19

Oxazolidinone–pyridine-substituted antibacterial agents.

Figure 20

Oxazolo[4,5-b]pyridines containing antibacterial agents with remarkable activity.

Figure 21

Pyrazolo[3,4-b] pyridine–bearing compounds with significant effect against various Gram-positive and Gram-negative bacterial strains.

Figure 22

Antibacterial dihydropyridines with thiazole moiety.

Figure 23

Highly potent antibacterial agents against staphylococcal infections.

Figure 24

Highly potent antitubercular compounds (43–45) with MIC values (µg/mL) against M. bovis BCG.

Figure 25

Pyridine-containing drugs against mycobacteria.

Figure 26

2(1-adamantylthio) pyridine derivatives with potent antimicrobial activity.

Figure 27

Highly active antimalarial pyridyl–indole hybrids.

Figure 28

Highly potent antimalarial pyridine-containing fosmidomycin derivative.

Figure 29

Pyridine/dihydropyridine-containing drugs in the market for HIV/AIDS treatment.

Figure 30

Pyridine–furan hybrid compounds with 50% reduction in viral titer against adenovirus 7 strain.

Figure 31

Potent antiviral compound 59 with activity against H5N1 influenza virus.

Figure 32

Antiviral GAK inhibitors containing isothiazolopyridine scaffold.

Figure 33

Antiviral compounds capable of targeting cyclin G–associated kinase of dengue virus.

Figure 34

Antiviral compounds with high GAK-binding affinity.

Figure 35

FDA-approved oxicam-class NSAIDs for musculoskeletal disorders, such as osteoarthritis and rheumatoid arthritis.

Figure 36

Commercially available NSAIDs containing the pyridine ring.

Figure 37

Indolyl pyridines (67–68) and dihydropyridine-containing compounds (69–71) with remarkable anti-inflammatory activity in animal models.

Figure 38

Thienopyridine derivatives (72–75) with anti-inflammatory and immunomodulatory profiles. IC₅₀ values correspond to inhibition of NO production on murine RAW264.7 macrophages.

Figure 39

Highly potent anti-inflammatory compounds.

Figure 40

11β-HSD1 inhibitors against diabetes mellitus.

Figure 41

Coumarin-fused pyridines with potent α-glucosidase activity.

Figure 42

Pyridine- or dihydropyridine-containing drug-repurposing candidates for treatment of neurodegenerative diseases.

Figure 43

Structure of the wide-spectrum neuroprotective drug nimodipine.

Figure 44

Highly potent AChE inhibitor.

Figure 45

Structure of naturally occurring huperzine A.

Figure 46

Compound 87 is capable of increasing expression of the GAD₆₇ enzyme in the hippocampus.

Figure 47

Antiparkinsonian activity of compounds 88and 89were comparable to reference drugs.

Figure 48

Structure of glutapyrone (left) and tauropyrone (right).

Figure 49

Pyroxicam binds with water-channel AQP4 to prevent cerebral ischemia.

Figure 50

Neuroprotective agent.

Figure 51

Neurogenically active pyridine alkaloids isolated from Senna and Cassia spp.

Figure 52

Pyridine-containing anticancer drugs in FDA database.

Figure 53

FDA-approved kinase inhibitors with pyridine scaffolds.

Figure 54

Pyridine–thiazole hybrids with remarkable anticancer effect in MCF7 breast adenocarcinoma.

Figure 55

Pyrazolo[3,4-b] pyridine- and dihydropyridine-derived compounds.

Figure 56

Oncology drugs for leukemia recently approved by the FDA.

Figure 57

Substituent effect on cytotoxicity by pyridine–indole hybrid compounds.

Figure 58

1,4-Dihydropyridine-containing benzylpyridinium moieties with remarkable anticancer activity.

Figure 59

Fused heterocyclic derivatives containing pyridine moieties.

Figure 60

Tetralin–pyridine hybrids.

Figure 61

Highly potent anticancer compound with PDE3-inhibitory effect.

Figure 62

Antitumor agents with telomerase-inhibitory effects.

Figure 63

Compounds with remarkable activity against HepG2 liver cancer cells.

Figure 64

Pyridine–pyrimidine hybrid ring system containing compound 126 with inhibitory effects against NCI60 cell lines.

Figure 65

Isonicotinic ester containing compounds 127 and 128.

Figure 66

p-cymene–ruthenium complex 130 with submicromolar anticancer activity against ovarian cancer cell lines.

Figure 67

Structure simplification in pyridine–isatin hybrids resulted in better IC₅₀ values.

Figure 68

[1,2,4]Triazolo[1,5-a]pyridinylpyridine–containing highly potent anticancer agent.

Figure 69

Diphenyl 1-(pyridin-3-yl)ethylphosphonate–containing anticancer agents.