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Review
. 2023 Oct 29;15(11):2554.
doi: 10.3390/pharmaceutics15112554.

The Role of Five-Membered Heterocycles in the Molecular Structure of Antibacterial Drugs Used in Therapy

Aura Rusu  1 , Ioana-Maria Moga  1 , Livia Uncu  2 , Gabriel Hancu  1
Affiliations
Review

The Role of Five-Membered Heterocycles in the Molecular Structure of Antibacterial Drugs Used in Therapy

Aura Rusu et al. Pharmaceutics. .

Abstract

Five-membered heterocycles are essential structural components in various antibacterial drugs; the physicochemical properties of a five-membered heterocycle can play a crucial role in determining the biological activity of an antibacterial drug. These properties can affect the drug's activity spectrum, potency, and pharmacokinetic and toxicological properties. Using scientific databases, we identified and discussed the antibacterials used in therapy, containing five-membered heterocycles in their molecular structure. The identified five-membered heterocycles used in antibacterial design contain one to four heteroatoms (nitrogen, oxygen, and sulfur). Antibacterials containing five-membered heterocycles were discussed, highlighting the biological properties imprinted by the targeted heterocycle. In some antibacterials, heterocycles with five atoms are pharmacophores responsible for their specific antibacterial activity. As pharmacophores, these heterocycles help design new medicinal molecules, improving their potency and selectivity and comprehending the structure-activity relationship of antibiotics. Unfortunately, particular heterocycles can also affect the drug's potential toxicity. The review extensively presents the most successful five-atom heterocycles used to design antibacterial essential medicines. Understanding and optimizing the intrinsic characteristics of a five-membered heterocycle can help the development of antibacterial drugs with improved activity, pharmacokinetic profile, and safety.

Keywords: antibacterials; antibiotics; biological activity; drug design; drug discovery; five-membered heterocycles; heterocycles; nitrogen heterocycles; oxygen heterocycles; sulfur heterocycles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 14
Figure 14
Cephalosporins whose chemical structure includes a tetrazole heterocycle: (a) Cefazolin (1st generation), (b) Cefamandole (2nd generation), (c) Cefonicid (2nd generation), (d) Cefotetan (3rd generation), (e) Cefmetazole (3rd generation), and (f) Cefoperazone (3rd generation) [29,31,117].
Figure 1
Figure 1
Chemical structure of carbapenems with the highlighted pyrrolidine nucleus: (a) doripenem, (b) ertapenem, and (c) meropenem.
Figure 2
Figure 2
Chemical structure of cephalosporins with the highlighted pyrrolidine nucleus: (a) cefepime and (b) cefiderocol [31,42].
Figure 3
Figure 3
Chemical structure of (a) ceftobiprole and (b) ceftobiprole medocaril (prodrug), with the highlighted pyrrolidine nucleus [48].
Figure 4
Figure 4
Chemical structures of fluoroquinolones with the highlighted pyrrolidine nucleus.
Figure 5
Figure 5
Chemical structure of lincosamides with the highlighted pyrrolidine nucleus: (a) lincomycin and (b) clindamycin.
Figure 6
Figure 6
Chemical structure of tetracyclines with the highlighted pyrrolidine nucleus: (a) rolitetracycline and (b) eravacycline.
Figure 7
Figure 7
The molecular structure of Rifaquizinone (TNP-20292) with highlighted pyrrolidine heterocycle [82,83].
Figure 8
Figure 8
Telithromycin, chemical structure and atoms numbering by the IUPAC name.
Figure 9
Figure 9
Chemical structures of (a) azomycin, (b) metronidazole, and (c) general chemical structure of 5-nitroimidazoles used in therapy.
Figure 10
Figure 10
Chemical structure of beta-lactamase inhibitors with the highlighted 2-imidazolidinone heterocycle: (a) Relebactam and (b) Durlobactam.
Figure 11
Figure 11
Tautomeric forms: (a) 1H-1,2,3-Triazole, (b) 2H-1,2,3-Triazole, (c) 4H-1,2,3-Triazole, and amphoteric behavior of 1,2,3-triazole [1,24].
Figure 12
Figure 12
The chemical structure of tazobactam.
Figure 13
Figure 13
Tetrazole forms: (a) 1H-tautomer, (b) 2H-tautomer, (c) 5-monosubstituted, (d) 1,5-disubstituted, and (e) 2,5-disubstituted [24,109].
Figure 15
Figure 15
Oxacephalosporins the chemical structure of which includes a tetrazole heterocycle: (a) Latamoxef (1st generation), and (b) Flomoxef (2nd generation) [29,123,124].
Figure 16
Figure 16
Structural differences between (a) linezolid, (b) tedizolid, and (c) tedizolid phosphate; the morpholine ring in linezolid was replaced with a pyridine and a methyl tetrazole ring in tedizolid [31,128,130].
Figure 17
Figure 17
Chemical structure of radezolid with highlighted triazole heterocycle.
Figure 18
Figure 18
Cephalosporins: (a) Cefuroxime and (b) Cefuroxime axetyl (acetyoxyethyl ester of cefuroxime), whose chemical structure include a furan heterocycle.
Figure 19
Figure 19
Nitrofurans, the chemical structure of which includes a furan heterocycle: (a) Furazolidone, (b) Nifuroxazide, (c) Nitrofurantoin, and (d) Nitrofurazone.
Figure 20
Figure 20
Ranbezolid, the chemical structure of which includes a furan heterocycle.
Figure 21
Figure 21
Isoxazolyl penicillins including 1,2-oxazole heterocycle in their molecular structures: (a) Oxacillin, (b) Cloxacillin, (c) Dicloxacillin, and (d) Flucloxacillin.
Figure 22
Figure 22
Chemical structure depiction of Cycloserine.
Figure 23
Figure 23
Chemical structure depiction of Posizolid.
Figure 24
Figure 24
Chemical structure depiction of Zoliflodacin.
Figure 25
Figure 25
Sulfonamides including 1,2-oxazole heterocycle in their molecular structures: (a) Sulfisoxazole, (b) Sulfisoxazole acetyl, and (c) Sulfamethoxazole.
Figure 26
Figure 26
Carboxypenicillins including thiophene heterocycle in their molecular structures: (a) Ticarcillin and (b) Temocillin.
Figure 27
Figure 27
Cephalosporins including thiophene heterocycle in their molecular structures: (a) Cephaloridine, (b) Cephalotine, and (c) Cefoxitin.
Figure 28
Figure 28
The thiazolidine heterocycle (purple) depiction in (a) Penam bicycle, (b) Penicillins molecular structure, and (c) Sulbactam.
Figure 29
Figure 29
The thiazole heterocycle (purple) depiction in (a) Aztreonam and (b) Carumonam molecular structure.
Figure 30
Figure 30
The thiazole heterocycle (purple) depiction in (a) Pirazmonam and (b) Tigemonam molecular structure.
Figure 31
Figure 31
The thiazole heterocycle (purple) depiction in (a) Sulfathiazole and (b) Phthalylsulfathiazole molecular structure.
Figure 32
Figure 32
Cephalosporins including thiadiazole heterocycle in their molecular structures: (a) Cefozopran, and (b) Ceftaroline fosamil.
Figure 33
Figure 33
Sulfamethizole molecular structure highlighting 1,3,4-thiadiazole ring.
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