Prescribed Drugs Containing Nitrogen Heterocycles: an Overview Cite This: RSC Adv., 2020, 10, 44247 Majid M
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RSC Advances View Article Online REVIEW View Journal | View Issue Prescribed drugs containing nitrogen heterocycles: an overview Cite this: RSC Adv., 2020, 10, 44247 Majid M. Heravi * and Vahideh Zadsirjan Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biologically active compounds are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top Received 28th October 2020 prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical Accepted 23rd November 2020 applications and their selected synthetic pathways. It is worth mentioning that the reported examples are DOI: 10.1039/d0ra09198g actually limited to current top selling drugs, being or containing N-heterocycles and their synthetic rsc.li/rsc-advances information has been extracted from both scientific journals and the wider patent literature. Creative Commons Attribution 3.0 Unported Licence. 1. Introduction chloroquinine, azidothymidine and anti-pyrine. Furthermore, most of the vitamins, nucleic acid, enzymes, co-enzymes, hormones, and 13 Medicinal and pharmaceutical chemistry are disciplines at the alkaloids contain N-based heterocycles as scaffolds. intersection of chemistry, especially synthetic organic chemistry, and Due to exhibiting diverse biological activities, nitrogen pharmacology and various other biological specialties, leading to the heterocyclic compounds have always been attractive targets to design, chemical synthesis and development of bio-active molecules, synthetic organic chemists. Since, several of them are prevalent for being approved as prescribed and market purchasable pharma- in natural products, especially alkaloids, they have received ceutical agents. Heterocyclic compounds, as the most important much attention of synthetic community, especially those who This article is licensed under a 14 organic compounds, are frequently present in molecules of interest are engaged with the total synthesis of natural products. As in medicinal chemistry.1 Among them, nitrogen containing hetero- a result, the vast number of nitrogen heterocyclic compounds cycles are of great importance to life science, since they are abundant have been under continuous investigations from different Open Access Article. Published on 15 December 2020. Downloaded 10/6/2021 4:16:25 PM. in nature, existing as subunits in several natural products, for points of view thus, found applications in pharmaceutical 15,16 example vitamins, hormones and antibiotics. Some representative research and drug discovery. Recently, N-based heterocycles alkaloids and other nitrogen containing natural products, showing have attracted much interest of medicinal chemists and biolo- diverse biological activities, and several of them are even prescribed gists due to broad range of biological activities and plentiful 17 drugs such as serotonin,2 thiamine, which is also called vitamin B1,3 applications in the extensive elds of pharmacy. atropine,4 notorious morphine,5 codeine, (greater benetmaybe FDA databases has revealed that about 60% of unique small- gained when it is combined with acetaminophen or a nonsteroidal molecule drugs, comprise N-based heterocycles, showing the anti-inammatory drug (NSAID) such as aspirin or ibuprofen),6 structural signicance of N-based heterocycles in drug design 18 papaverine,7 coniine,8 caffeine9 and nicotine.10 and drug discovery. The prevalence of N-heterocyles in bio- Furthermore, N-based heterocycles are indispensable diet logically active compounds can be attributed to their stability components such as thiamin (vitamin B1), riboavin (vitamin B2), and operational efficiency in human body and the fact of that pyridoxol (vitamin B6), nicotinamide (vitamin B3).11,12 Nitrogen- the nitrogen atoms are readily bonded with DNA through containing heterocyclic compounds are not only present as the hydrogen bonding. As a matter of fact, anti-cancer activities of backbone in several biologically active natural products used as N-based heterocycle agents are largely due to their tendency of 19 traditional medications or approved prescribed drugs, but some of interaction with DNA via hydrogen bonding. their synthetic derivatives in different sizes, nowadays are prescribed In 2014 Njardarson et al. published the rst comprehensive 16 and market purchasable drugs. The most famous are, diazepam, analysis of the nitrogen based heterocycles. This analysis isoniazid, chlorpromazine, metronidazole, barbituric acid, captopril, showed that indeed about 60% of small-molecule drugs contain a N-based heterocycle as common architectural cores. In 2011, Baumann et al. presented an overview of the key pathways to the Department of Chemistry, School of Science, Alzahra University, PO Box 1993891176, synthesis of the best-selling ve-membered ring heterocyclic Vanak, Tehran, Iran. E-mail: [email protected]; [email protected]; Fax: medications regardless of their kinds of heterocycles.20 In the +98 21 88041344; Tel: +98 21 88044051 This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10,44247–44311 | 44247 View Article Online RSC Advances Review following, in 2013 the same authors presented an overview on common of such pharmaceuticals, classifying them in accor- the synthetic pathways to the best selling drugs comprising six- dance of their size of N-based heterocycles, in, four, ve, six, and membered heterocyclic systems.21 In 2018, Ramazani and co- seven-membered rings. Moreover, the fused, bridged bicyclic workers15 presented the recent advances in nitrogen-based nitrogen heterocycles have been also covered. heterocyles as useful cancer chemotherapy agents. Cancer is one of the foremost roots of death, globally. It is the result of mutation of the cells which regulate the genes and protein. 2. Synthesis of nitrogen prescribed Although, surgery and radiotherapy are the current therapy drugs having several drugs are also used as anticancer agents in spite of their undesired side effects. Some analogues of new isosteviol-fused 2.1 Four-membered heterocycles pyrazoline, ursolic acid linked triazole or D-ribose linked exhibit In general antimicrobial drugs are recognized as bacteriostatic (i.e., 22 anticancer activity at the nanomolar range. Furthermore tetracyclines, sulfonamides) and as antibacterial (i.e., penicillin). showing segment resemblance with histidine imidazole mole- Beta-lactam antibiotics are categorized to four groups. They are cule N-based-heterocycles can be linked with protein molecules penicllins, cephalosporins, monobactams, and carbapenems. They ff more easily than some other heterocyclic sca olds, thus, these all comprise a four-membered beta-lactam ring that is essential for types of N-heterocyclics are the most promising drugs for being displaying their antibactericidal activities. In 1929, penicillin was 23 designed and screened as anti-cancer drugs. We are interested explored by Sir Alexander Fleming, who observed that one of his 24 in heterocyclic chemistry, especially those containing nitrogen experimental cultures of staphylococcus was polluted with fungus 25–33 atom. that caused the bacteria to lyse.43,44 Since fungus belonged to the 24 We are interested in heterocyclic chemistry, especially family penicillium, he called this bactericidal substance penicillin. 25–33 those containing nitrogen atom. In recent years, our group A decade later, a research group at Oxford University could isolated has also focused on the applications of name reactions in the a crude substance built of a few low-molecular substances that were Creative Commons Attribution 3.0 Unported Licence. total synthesis of natural products containing nitrogen hetero- named penicillins (F, G, K, O, V, X). Among the various penicillins 34–42 cycles, showing diverse biological activities. Armed with (F,G,K,O,V,X),penicillinG(benzylpenicillin), was found the most these experiences, in this review we try to highlight the medical effective. Since then, penicillin G, is used as an antibiotic to treat usages and selected synthetic pathways of approved and market a number of bacterial infections.45 purchasable prescribed medications, containing nitrogen There are three main and remarkable stages to the biosyn- based-heterocycles. Having collected and categorized of about thesis of penicillin G 7 (benzylpenicillin). Initially, three amino 640 medications, comprising a based-nitrogen heterocycle, we acids-L-a-aminoadipic acids, L-cysteine, L-valine are condensed had to be selective and sumarritive, limiting ourselves to most to a tripeptide.46–48 Before the generation of this tripeptide, the This article is licensed under a Open Access Article. Published on 15 December 2020. Downloaded 10/6/2021 4:16:25 PM. Scheme 1 Synthesis of penicilin G 7. 44248 | RSC Adv.,2020,10, 44247–44311 This journal is © The Royal Society of Chemistry 2020 View Article Online Review RSC Advances amino acid L-valine is subjected to epimerization to turn out to be The total synthesis of penicillin V 20 was rst achieved in 49,50 D-valine 3. This tripeptide is called d-(L-a-aminoadipyl)-L- 1948. It started with racemic valine 3, which was effectively cysteine-D-valine (ACV) 4. The above epimerization and conden- converted