A very high proportion of approved drugs contain nitrogen-containing heterocyclic structures. Taking the period from 2013 to 2023 (11 years) as an example, 82% of all approved drugs featured at least one nitrogen-containing heterocycle. This article presents the 35 most frequently occurring nitrogen-containing heterocyclic frameworks found among the 321 drugs approved during that time.
- Pyridine is the most common nitrogen-containing heterocycle, ranking first overall. Fifty-four drugs include a pyridine ring, most of which have a substituent at the 2-position of the ring. Among these, disubstituted pyridines are the most prevalent (55%), with the 2,5-disubstituted pattern being the most frequently observed.
- Piperidine ranks second among nitrogen-containing heterocycles, appearing in 40 approved drugs-just behind pyridine. Most piperidine-containing drugs feature substituents at the 1-position or 4-position, or at both sites.
- Pyrrolidine occurs with a frequency comparable to that of piperidine, also found in 40 approved drugs. In most cases, the nitrogen atom (position 1) of the pyrrolidine ring is substituted. A majority (53%) are disubstituted, with the 1,2-disubstituted pattern being the most common.
- Piperazine ranks fourth among nitrogen-containing heterocycles, appearing in 36 novel small-molecule drugs. Substitution on both nitrogen atoms is common, with the 1,4-disubstituted piperazine pattern being the most prevalent.
- Pyrimidine ranks fifth, identified in 25 new small-molecule drugs. Most pyrimidine-containing drugs are trisubstituted (46%), followed by disubstituted ones (38%). The 2,4,5-trisubstituted pyrimidine pattern is the most frequently observed.
- Indole ranks sixth, with 21 small-molecule indole drugs and diagnostic agents approved, including four radiometal chelate diagnostic agents. Most indole-containing drugs are monosubstituted (41%) or trisubstituted (36%), with substitution at the 3-position being the most common (41%).
- Pyrazole ranks seventh, with 20 unique small-molecule drugs. Half of the pyrazole-containing drugs are disubstituted, and the 1,4-disubstituted configuration predominates.
- Imidazole ranks eighth, appearing in 18 drugs. Half of these imidazole-containing drugs are disubstituted, with 2,4-disubstitution being the most frequent pattern.
- Morpholine ranks ninth, identified in 13 new small-molecule drugs. Most morpholine-containing compounds are monosubstituted at the nitrogen atom, and among them, fostamatinib-a tyrosine kinase inhibitor approved in April 2018-is one of the most representative examples.
- Benzimidazole ranks tenth, with 10 new small-molecule drugs. Unlike other top-ten nitrogen heterocycles, benzimidazole exhibits unusual substitution patterns-most are trisubstituted or tetrasubstituted, with substitutions at the 2-, 5-, and 6-positions being the most common.
- 1,2,4-Triazole is a five-membered nitrogen-containing heterocycle widely used in antifungal, antibacterial, and anticancer drugs. Its strong hydrogen-bonding ability and metabolic stability make it a valuable scaffold in pharmaceuticals such as fluconazole and voriconazole.
- Thiazole is a sulfur- and nitrogen-containing heterocycle often found in vitamins (like thiamine) and antibiotics. It contributes to bioactivity, stability, and enzyme-binding affinity in a variety of therapeutic agents.
- Uracil is a pyrimidine base essential to RNA structure and serves as a core motif in anticancer and antiviral drugs, including fluorouracil derivatives used in chemotherapy.
- 2-Pyridone is a versatile lactam-like nitrogen heterocycle that forms strong hydrogen bonds and is often used in kinase inhibitors, antibacterial, and anti-inflammatory drugs.
- Tetrahydroisoquinoline is a bicyclic nitrogen heterocycle found in many natural alkaloids. It exhibits significant neuropharmacological activity and is used in the design of anticancer and cardiovascular drugs.
- Quinoline is an aromatic nitrogen heterocycle widely recognized for its use in antimalarial and antibacterial drugs, such as chloroquine and ciprofloxacin, as well as in anticancer agents.
- Quinazoline is a fused nitrogen heterocycle commonly used in tyrosine kinase inhibitors for cancer treatment, including gefitinib and erlotinib. It enhances target selectivity and bioavailability.
- Pyrrolopyrimidine is a fused heterocycle mimicking purine bases, widely applied in kinase inhibitor development and antiviral drug discovery due to its ability to modulate nucleic acid-binding proteins.
- Pyrazolopyrimidine structures are dual-ring heterocycles found in anti-inflammatory and anticancer agents. They provide improved receptor affinity and metabolic stability.
- Pyrrolopyridine is a fused bicyclic heterocycle that serves as a bioisostere for indoles and is frequently used in kinase inhibitors and central nervous system (CNS) drugs.
- Purine is a fundamental bicyclic heterocycle forming the basis of DNA and RNA nucleotides. It is central to many drugs, including antivirals (like acyclovir) and immunosuppressants.
- Indazole is a nitrogen-rich bicyclic ring system used in anticancer, anti-inflammatory, and analgesic drug discovery, prized for its balance between lipophilicity and metabolic stability.
- 2-Pyrrolidone is a lactam heterocycle used as a solubilizing and bioactive scaffold in nootropic and antiepileptic drugs such as piracetam and levetiracetam.
- 1,3-Oxazinane is a six-membered heterocycle containing both nitrogen and oxygen atoms, applied in antiviral and antibacterial drug design for its hydrogen-bonding and metabolic stability properties.
- Quinoxaline is a bicyclic nitrogen heterocycle with potent antimicrobial and anticancer activity, often used in enzyme inhibitors and fluorescent probes.
- Azetidine, or azacyclobutane, is a four-membered nitrogen heterocycle used to increase conformational rigidity and improve drug bioavailability in modern medicinal chemistry.
- Quinolin-2-one is an aromatic lactam structure known for its role in developing anticonvulsant, anti-inflammatory, and CNS-active agents.
- Isoquinoline is a structural isomer of quinoline found in many natural alkaloids. It serves as a core scaffold in antihypertensive, anticancer, and antimalarial drugs.
- Tetrazole is a nitrogen-rich ring that acts as a bioisostere for carboxylic acids. It enhances drug solubility and metabolic stability, widely used in angiotensin II receptor blockers (e.g., losartan).
- Isoxazole is a five-membered ring with oxygen and nitrogen atoms, found in anti-inflammatory, anticonvulsant, and antimicrobial drugs, such as valdecoxib.
- DABCO is a bicyclic nitrogen compound known for its rigid framework and use as a catalyst or structural motif in enzyme inhibitors and chiral pharmaceuticals.
- Pyrazolopyridine is a fused heterocycle used in anti-inflammatory, antiviral, and kinase inhibitor drugs, offering strong receptor selectivity.
- Azepane, a seven-membered nitrogen-containing ring, is used in CNS-active and antidepressant drugs to improve solubility and receptor binding flexibility.
- Pyrrolotriazine is a tricyclic nitrogen heterocycle found in kinase inhibitors and anticancer agents, providing enhanced potency and metabolic resistance.
- Thiadiazole is a sulfur- and nitrogen-containing five-membered ring used in antimicrobial, antitumor, and anti-inflammatory drugs for its strong electron-withdrawing and pharmacophoric properties.
Conclusion
Nitrogen-containing heterocycles are the cornerstone of modern medicinal chemistry, forming the structural backbone of most small-molecule drugs. From simple rings like pyridine and piperidine to complex fused systems such as quinazoline and pyrrolopyrimidine, these compounds play vital roles in enhancing biological activity, selectivity, and pharmacokinetic profiles. Their diverse chemical reactivity and ability to mimic natural biomolecules make them indispensable in drug discovery across therapeutic areas including oncology, infectious diseases, and neurology. As synthetic methods and computational design advance, the exploration of novel nitrogen heterocycles will continue to drive innovation in next-generation pharmaceuticals.
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