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Review

Beyond Peptides and Peptidomimetics: Natural Heteroaromatic Amino Acids in the Synthesis of Fused Heterocyclic Frameworks for Bioactive Agents

by
Isis Apolo Silveira de Borba
1,
Jamile Buligon Peripolli
2,
Angélica Rocha Joaquim
3 and
Fernando Fumagalli
3,*
1
Pharmaceutical Sciences Graduate Program, Federal University of Santa Maria, Santa Maria 97105-900, RS, Brazil
2
Pharmacy Course, Federal University of Santa Maria, Santa Maria 97105-900, RS, Brazil
3
Department of Pharmacy, Health Sciences Centre (DFI/CCS), Federal University of Santa Maria, Santa Maria 97105-900, RS, Brazil
*
Author to whom correspondence should be addressed.
Organics 2025, 6(2), 23; https://doi.org/10.3390/org6020023
Submission received: 30 March 2025 / Revised: 2 May 2025 / Accepted: 15 May 2025 / Published: 21 May 2025
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Abstract

Heterocycle cores are widely used in medicinal chemistry for developing bioactive compounds. In this scenario, using cheap and accessible starting material to build these heterocycles is desirable to obtain new drug candidates for cost-efficient processes. One easily accessible source of starting material are amino acids. Usually, these compounds are employed in peptide synthesis, but their use for building heterocycle frameworks presents another appealing opportunity. Therefore, this review highlights the application of histidine and tryptophan, two heteroaromatic amino acids, in fused heterocyclic scaffold synthesis and their use in bioactive compounds.

Graphical Abstract

1. Introduction

Histidine and tryptophan are heteroaromatic amino acids with imidazole and indole rings in their structure, respectively. These two rings are among the most common rings in drugs and lead-like drugs [1,2,3], highlighting the potential application of these amino acids in the development of bioactive compounds.
The use of amino acids to make bioactive peptides and peptidomimetic compounds is very common [4,5,6,7,8,9], but they are also present in the biosynthetic pathways of some important naturally occurring alkaloids. Representative examples of alkaloids derived from histidine and tryptophan are shown in Figure 1.
Spinacine, present in Panax ginseng [10], and Cucumopine, found in Agrobacterium rhizogenes [11,12], are examples of histidine derivatives formed by cyclization reaction in imidazole C-4 through Pictet–Spengler reaction. Also, this amino acid can be converted into its respective biogenic amine, histamine, and then undergo Pictet–Spengler cyclization to form, for example, Ageladine A, an important anti-angiogenic alkaloid [13].
Similar aspects can be observed for tryptophan-derivative alkaloids. Its biogenic amine, tryptamine, undergoes heterocyclization at indole C-4 to form physostigmine [14] and Pictet–Spengler-type reaction with secologanin to form strictosidine, a key intermediate in the biosynthesis of Yohimbine [15], an antagonist of α2-adrenergic receptors from the bark of the Pausinystalia yohimbe tree [16]. The antifungal [17] canthin-6-one derivative Nigakinone also comes from a Pictet–Spengler-type reaction and some oxidations to obtain the tetracyclic framework with cyclization into indole nitrogen [18]. Tryptophan can also undergo prenylation at indole C-4 to later be cyclized into the tetracyclic framework [19] present in ergometrine, a drug used in obstetrics to control postpartum bleeding [20].
Historically, natural products inspired medicinal chemistry and organic synthesis in developing several drugs [21,22]. And it was no different for these two amino acids, which are employed in the synthesis of a diverse set of bioactive heterocyclic frameworks. Therefore, considering the importance of histidine and tryptophan beyond peptides and peptidomimetics, this review brings the leading findings in the synthesis of fused heterocycles prepared from these two heteroaromatic amino acids and their application in bioactive compounds.

2. Fused Heterocyclic Scaffolds from Histidine

The most common fused heterocycle framework prepared from histidine is the tetrahydro-imidazo [4,5-c]pyridine core (Figure 2), which is present in the natural product Spinacine, an alpha-amino acid of ginseng (Panax ginseng) and spinach (Spinacia oleracea) [23]. Normally, this structural pattern is prepared using aldehyde or aldehyde-related compounds in acidic conditions, which is known as the Pictet–Spengler reaction [24,25,26]. However, basic conditions can also be used (Figure 2) [27,28,29,30]. This reaction involves heterocyclization at imidazole C-4, and the yield varies according to the conditions and the aldehyde used (Figure 2). One interesting fact regarding this tetrahydro-imidazo [4,5-c]pyridine core is that the C-6 carboxyl group of the Spinacine prevents the ring opening necessary for the racemization [31].
Another reactivity aspect of tetrahydro-imidazo [4,5-c]pyridine framework is that if this core has an aryl group at the core C-4, a hydrogenolysis in methanol at reflux using ammonium formate rapidly converts it to 4(5)-benzyl-L-histidine [33]. This is an important way to prepare 4-benzyl histidine derivatives.
The functionalization of histidine imidazole ring can also be accomplished after amine protection by a ring cyclization with 1,1′-carbonyldiimidazole (CDI) to form a 5-oxo-5,6,7,8-tetrahydroimidazo [1,5-c]pyrimidine core. After that, the non-substituted imidazole nitrogen can be alkylated; then, the protecting group can be removed to form scaffold 5. (Figure 3) [34,35]. This protection can also be accomplished by phosgene use [36].
The tetrahydro-imidazo [4,5-c]pyridine core prepared from histidine can undergo a dehydrogenation reaction to obtain the full aromatic imidazo [4,5-c]pyridine core 6 (Figure 4). Normally, in this reaction, a decarboxylative aromatization takes place using selenium dioxide [30], sulfur [37,38], 2-Iodoxybenzoic acid (IBX), or octasulfur [29]. When an ester of tetrahydro-imidazo [4,5-c]pyridine is reacted with selenium dioxide activated by trimethylsilyl polyphosphate (PPSE) in carbon tetrachloride, [39] the aromatic imidazo [4,5-c]pyridine core formed keeps the ester group [25,26].
The direct formation of aromatic imidazo [4,5-c]pyridine core from histidine was already identified from Maillard reaction conditions, in which the heating of glucose with histidine forms 2-acetyl- and 2-propionyl imidazo [4,5-c]pyridine (Figure 5) [40,41]. The reaction of histidine with another monosaccharide, D-Ribose, provided a 5–5 fused ring system 8 that showed glutathione recovery capacity (GCR) [42] and, therefore, can be used to increase the protective effects in events of prolonged and exacerbated oxidative stress [43].
The tetrahydro-imidazo [4,5-c]pyridine and imidazo [4,5-c]pyridine cores obtained from histidine were already employed in a diverse set of bioactive compounds (Figure 6). The most common application is in anticancer agents, such as kinase inhibitors (11 and 12, Figure 6) [26,44] and compounds 9a–b with anti-angiogenesis activity [29]. Diabetes vascular complications mediated by SSAO (semicarbazide-sensitive amine oxidase) can be treated or prevented by the use of some tetrahydro-imidazo [4,5-c]pyridine derivatives (10, Figure 6) [28]. In addition, some hydroxamate derivatives (14, Figure 6) from the imidazo [4,5-c]pyridine core showed anti-HIV activity [25] and the 4-phenyl derivative (13, Figure 6) showed good inhibition of [3H]diazepam binding to rat cerebral cortical membranes [30].
Up until now, the most common fused heterocyclic scaffolds from histidine are the 5-6 and 5-5 bicyclic cores. However, some other fused frameworks were already prepared from histidine. A hydantoin-5-6-5-fused ring system can be prepared from the tetrahydro-imidazo [4,5-c]pyridine core 3a shown above. By reacting this core with isocyanate, an imidazolidine-dione ring is formed fused to the tetrahydro-imidazo [4,5-c]pyridine. This tricyclic fused system (15, Figure 7) has potential antitumor activity by HDAC (histone deacetylase) inhibition, [45], and it was already proven not to have activity against the histamine-H3 receptor [46].
Another tricyclic ring system can be formed by reacting tetrahydro-imidazo [4,5-c]pyridine core with chloroacetyl chloride followed by methylamine addition (Figure 8). The diketopiperazine-5-6-6 ring system at 16 showed some PDE5 (phosphodiesterase type 5) inhibition that can have utility in a variety of therapeutic areas, including the treatment of cardiovascular disorders and erectile dysfunction [27].
Histidine can also be used to prepare centrocountins-related compounds through a one-pot cascade reaction [47]. Centrocountins are tetracyclic indole-quinolizine, whose synthesis was inspired by indole alkaloid natural products and has potential biological applications, such as anticancer activity [48]. The bellow quinolizine ring formation (Figure 9) involves a Pictet–Spengler step, followed by an aza-Michael addition; the N-methylated histidine reacts better than the NH counterpart [47].
A recent study described another quinolizine-like framework from histidine (Figure 10). Genihistidine A and B were described as products in the reaction of this amino acid with Genipin, a monoterpenoid extracted from Gardenia jasminoides, a herb commonly used in traditional Chinese medicine. Genipin is also involved in the formation of gardenia blue (GB) pigment, as a natural blue pigment, which is utilized as a natural food additive in numerous countries [49]. Genihistidine B also has some antiproliferative activity against colon cancer [50].
Ultimately, a more extended ring-fused system was prepared using a tetrahydro-imidazo [4,5-c]pyridine core obtained from histidine and another tricyclic system prepared from tryptophan. This reaction formed a new hexacycle diketopiperazine framework 20 (Figure 11), which showed an anti-proliferative effect added to the inhibition in the migration and invasion of tumor cells and an in vivo anti-metastasis effect [51].

3. Fused Heterocyclic Scaffolds from Tryptophan

An intersection application of both heteroaromatic amino acids, histidine, and tryptophan, can be already observed above (Figure 11); however, in this section, data from fuse heterocyclic frameworks prepared from tryptophan are presented. For clarity, we have divided the findings according to the indole position of the cyclization and the ring system size formed. Also, the biological applications, when existing, are presented below.

3.1. Tricyclic-Fused Heterocyclic Scaffolds by Heterocyclization at Indole C-2

3.1.1. 6-5-6-Fused Ring System

Similarly to histidine, the most common heterocyclization reaction with tryptophan involves a Pictet–-Spengler-like reaction to form a tetrahydro-1H-pyrido [3,4-b]indole core (Figure 12) [52,53]. In this reaction, the tryptophan undergoes condensation with an aldehyde or ketone, followed by ring closure [54,55]. For the reaction, an acid is usually used, such as glacial acetic acid [56,57,58,59,60], sulfuric acid [61,62,63,64,65,66,67], p-toluene sulfonic acid (PTSA) [68,69], and trifluoroacetic acid (TFA) [70,71]. Same as for histidine, the basic conditions are also employed for the synthesis of tetrahydro-1H-pyrido [3,4-b]indole framework [72,73,74,75,76]. Normally, these reactions happen at high temperatures and in good yields and are broadly applied in the preparation of β-carboline alkaloids [77,78].
The tetrahydro-1H-pyrido [3,4-b]indole core prepared from tryptophan can be oxidized to the aromatic fused system 21 using different strategies (Figure 13 and Figure 14). The dehydrogenation keeping carboxylic group can be accomplished using trichloroisocyanuric acid (TCCA) in DMF [69], potassium permanganate in DMF [60,79,80,81,82,83,84,85,86,87,88,89,90], THF [68] or acetone [91,92], and sulfur [62,66,93,94,95,96,97,98,99,100] or octasulfur [101] in reflux of xylene. When manganese dioxide is used in toluene or benzene, reflux occurs an aromatization without decarboxylation of the ester group [75,102]. However, when free acid is on the tetrahydro-1H-pyrido [3,4-b]indole core, the use of manganese dioxide and sulfuric acid allows the decarboxylative aromatization [103,104]. A similar case happens when heating the tetrahydro-1H-pyrido [3,4-b]indole core in DMSO—the ester in the core prevents decarboxylative aromatization, but it occurs when a free acid is inside the molecule [105]. Under the same condition, when a secondary amine, e.g., tosyl, is substituted, a base addition is required for the aromatization [106].
Organics 06 00023 g013
Figure 13. Tetrahydro-1H-pyrido [3,4-b]indole core dehydrogenation. Conditions: (A) R1 = Me and R2 = aryl: TCCA, Et3N/ DMF; 0 °C-rt, 2 h [69]; (B) R1 = H or alkyl and R2 = H, alkyl or aryl: KMnO4, DMF, rt, 1–16 h [60,68,79,80,81,82,83,84,85,86,87,88,89,90,91,92]; (C) R1 = Me and R2 = H, alkyl or aryl: Sulfur or octasulfur, xylene, reflux, 8–48 h [62,66,93,94,95,96,97,98,99,100,101]; (D) R1 = Et and R2 = H: MnO2, Toluene, reflux [75,102]; (D) R1 = Me and R2 = alkyl or aryl: DMSO, 90–95 °C, 7–10 h [105,106].
Figure 13. Tetrahydro-1H-pyrido [3,4-b]indole core dehydrogenation. Conditions: (A) R1 = Me and R2 = aryl: TCCA, Et3N/ DMF; 0 °C-rt, 2 h [69]; (B) R1 = H or alkyl and R2 = H, alkyl or aryl: KMnO4, DMF, rt, 1–16 h [60,68,79,80,81,82,83,84,85,86,87,88,89,90,91,92]; (C) R1 = Me and R2 = H, alkyl or aryl: Sulfur or octasulfur, xylene, reflux, 8–48 h [62,66,93,94,95,96,97,98,99,100,101]; (D) R1 = Et and R2 = H: MnO2, Toluene, reflux [75,102]; (D) R1 = Me and R2 = alkyl or aryl: DMSO, 90–95 °C, 7–10 h [105,106].
Organics 06 00023 g013
Other conditions also give the aromatic pyrido [3,4-b]indole core (β-carboline core) by decarboxylative process (Figure 14). The organic base DBN (1,5-diazabicyclo [4.3.0]non-5-ene) was shown to be an efficient reagent for promoting the dehydrogenative/decarboxylative aromatization of tetrahydro-β-carbolines under air atmosphere [107]. The iodobenzene diacetate (IBD) [108] and N-chlorosuccinimide (NCS) [87,109] in DMF at room temperature are also efficient methods for decarboxylative oxidation of this core. On the other hand, iron(III) chloride needs air and higher temperature in DMF to obtain the aromatic core [110]. Potassium dichromate [111,112,113] and selenium dioxide [72,114] are the other two oxidizing agents that perform a decarboxylative aromatization in the reflux of acetic acid.
Organics 06 00023 g014
Figure 14. Decarboxylative aromatization of tetrahydro-1H-pyrido [3,4-b]indole core: (A) R = alkyl or aryl: DBN, air, 110 °C, 12h [107]; (B) PhI(OAc)2, DMF, rt, 2h [108]; (C) R = H, alkyl or aryl: NCS, TEA, DMF, rt, 30–45 min [87,109]. (D) R = H, alkyl or aryl: K2Cr2O7(aq), AcOH, reflux, 5 min–6 h [111,112,113]; (E) R = H: SeO2, AcOH, reflux, 12h [72,114]; (F) R = H, alkyl or aryl: FeCl3, DMF, 130 °C air (O2), 1 h [110].
Figure 14. Decarboxylative aromatization of tetrahydro-1H-pyrido [3,4-b]indole core: (A) R = alkyl or aryl: DBN, air, 110 °C, 12h [107]; (B) PhI(OAc)2, DMF, rt, 2h [108]; (C) R = H, alkyl or aryl: NCS, TEA, DMF, rt, 30–45 min [87,109]. (D) R = H, alkyl or aryl: K2Cr2O7(aq), AcOH, reflux, 5 min–6 h [111,112,113]; (E) R = H: SeO2, AcOH, reflux, 12h [72,114]; (F) R = H, alkyl or aryl: FeCl3, DMF, 130 °C air (O2), 1 h [110].
Organics 06 00023 g014
The β-carboline core can also be obtained directly from the reaction of tryptophan with another amino acid in the presence of iodine and trifluoracetic acid (Figure 15). For this reaction, decarboxylation, deamination, Pictet−Spengler reaction, and oxidation reactions proceeded sequentially [115].
As already mentioned, the 6-5-6-fused ring system is the most explored one in the literature, including its use in biological applications. Therefore, a diverse set of these compounds was selected and presented in Figure 16.
The tetrahydro-1H-pyrido [3,4-b]indole and pyrido [3,4-b]indole core (β-carboline) have been widely used in the development of antiproliferative agents against various cancer cell lines, including pancreatic (BxPC-3), cervical (HeLa), and prostate (PC3 and C4-2) cancers [59,81,107,115,116]. In addition, some of these compounds act as HDAC inhibitors [79,80], and 23 demonstrated anticancer activity by inhibiting topoisomerase I and kinesin spindle protein [100]. Derivatives of tetrahydro-9H-pyrido [3,4-b]indole also exhibit hypoglycemic properties comparable to or exceeding those of pioglitazone, suggesting their potential for diabetes treatment [117]. Compounds derived from β-carboline-triazine 27 have shown superior antileishmanial activity compared to sodium stibogluconate, with reduced toxicity, and have significant potential for the development of new therapeutic agents [92].
Moreover, β-carboline derivative 28 shows promising antiviral effects, with activity against HSV-1 and poliovirus [57], and has been investigated as a multifunctional acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease [94] and alcohol abuse [75]. In agriculture, compounds such as 26 stand out as potent antifungal agents against several phytopathogenic species, including Fusarium oxysporum, Rhizoctonia solani, and Botrytis cinerea [81,84,104].

3.1.2. 6-5-5-Fused Ring System

The hexahydropyrrolo [2,3-b]indole core 29 is common in bioactive natural products, such as physostigmine, a cholinesterase inhibitor used to treat glaucoma [118]. The pyrrolidinoindolines is usually obtained by the classical protocol of bromocyclization using N-bromosuccinimide without any other additives (Figure 17) [119,120]. Moreover, iodine(III)-mediated annulation provides tertiary chloride pyrrolo [2,3-b]indoline skeleton [121]. The tertiary alcohol derivative can be obtained directly by dye-sensitized photooxygenation of tryptophan [122] or unprotected tryptophan oxygenation by engineered enzyme [123].

3.1.3. 6-5-7-Fused Ring System

The seven-member-ring fused to indole is not the most explored framework from tryptophan, but some azepine derivatives were already prepared from this amino acid. For this reaction, an acyl-alpha-bromide in DCE and triflic acid provide the azepino [4,5-b]indole core 30 (Figure 18). The acylhydrazone derivative of this core showed some agricultural application due to their activity against the tobacco mosaic virus (TMV) [124]. The azepino [4,5-b]indole core can also be used as an intermediate in hetero-Diels–Alder cycloaddition [125].
A similar core with indole fused to azepinone can be obtained in a catalyst-free Ugi-three-component reaction (Ugi-3CR) using 2-formyl-L-tryptophan as a bifunctional building block (Figure 19) [126].

3.2. Tricyclic-Fused Heterocyclic Scaffolds by Heterocyclization at Indole C-4

The azepinone ring can also be fused to indole C-4 forming a tetrahydro-1H-azepino [5,4,3-cd]indol-1-one core 34. This core is present in natural products [127] and the FDA-approved drug Rucaparib (Figure 20), used to treat cancer [128]. Recently, rucaparib derivatives with the benzazepinone scaffold were described, using 2-aryl-tryptophan in a Pd-catalyzed remote C–H carbonylation, where molybdenum carbonyl was used as the source of the C=O (98% yield) (Figure 20) [129].

3.3. Polycyclic-Fused Scaffolds Involving Indole Nitrogen and C-2

Like histidine, the tryptophan-derived fused-ring system involving heteroaromatic nitrogen cyclization is less common. Among them, the tetracyclic core diaza-cyclopenta-fluorene-dione is present in some natural products, such as the cytotoxic alkaloid Chaetominine [130] and Versiquinazoline H [131]. A synthetic route for these alkaloids has already been developed, where the tetracyclic system 36 is obtained using DMDO in acetone or THF (Figure 21) [132,133].
Other hexacyclic or pentacyclic skeletons can be prepared from tryptophan through an initial Pictet–Spengler-like reaction, followed by oxidative cyclization and aromatization (Figure 22) [134]. This framework is very similar to an aryl hydrocarbon receptor (AhR) select modulator, 11-Cl-BBQ [135], which suppresses lung cancer cell growth and is under patent protection for this application [136].
The hexahydropyrrolo [2,3-b]indole core 29 is common in pyrrolidinoindoline natural products, a growing family of bioactive alkaloids. Pyrrolidinoindolines consist mainly of a majority of diketopiperazines (DKPs) and a minority of diketomorpholines (DKMs) (Figure 23) [137]. Nocardioazines B is a DKP marine-derived natural product, where the key step for the 7-fused-mebered-ring scaffold is diketopiperazine formation by amide coupling [138,139]. Similar occurs with the total synthesis of Javanicunines A, where the diketomorpholine is built by amide coupling and ester cyclization to obtain the 4-fused-mebered-ring scaffold of this natural product [137]. For both of these natural products, the key intermediate 3a-bromo hexahydropyrrolo [2,3-b]indole core is synthetically obtained from tryptophan (Figure 17). Another DKP pyrrolidinoindoline natural product, Brevianamide E, explored another synthetic strategy by preparing one amide before the hexahydropyrrolo [2,3-b]indole core formation and, then, a last cyclization to form the diketopiperazine [140].
Beyond the hexahydropyrrolo [2,3-b]indole core 29, the tetrahydro-1H-pyrido [3,4-b]indole 19 and pyrido [3,4-b]indole core (β-carboline, 22) are also used to prepared larger fused-ring systems. The tetrahydro-1H-pyrido [3,4-b]indole core has been used for the obtention of compounds fused with hydantoin and thiohydantoin rings (Figure 24) by reacting this core with isocyanate and isothiocyanate, respectively [54,141,142,143,144]. Monastroline (HR22C16) is an example of a bioactive compound with this skeleton, which is a cell-permeable non-tubulin-interacting mitosis inhibitor for cancer treatment [145,146].
The synthesis of tetrahydro-β-carboline fused to lactams is also reported and can be performed by different synthetic strategies. The condensation of tryptophan with dimethyl 2-oxopentanedioate as a key step to synthesize the natural product (+)-tabertinggine (Figure 25). This approach gave the (5S,11R)-39 as the major stereoisomer formed [147].
Five-membered heteroaromatic rings can also be built with a fourth ring fused to tetrahydro-β-carboline and β-carboline cores (Figure 26). The cyclization using dimethyl acetylenedicarboxylate (DMAD) in the presence of acetic anhydride gave the pyrrole-tetracyclic product 40 in 86%. This product after some steps gives an antitumor indolizino [6,7-b]indole 41 with multiple modes of action, including topoisomerase I and II inhibition [148]. Another antitumoral tetracyclic agent, 42a, can be prepared from β-carboline 22a forming an imidazole-fused-ring at 42 [149]. Depending on the desired position of the imidazole substituent, a different reactant is used. For the C-2-substituted pattern, an alfa-bromo-ketone in reflux of ethanol gives the desired product [148], while for the C-3-substituted pattern, an aldehyde together with triethylamine and octasulfur in a solution of DMSO/cyclohexane at high temperature affords the tetracyclic pattern [149].
Ultimately, a significantly explored tetracyclic framework from tryptophan is the diketopiperazine fused to the tetrahydro-β-carboline core 43 (Figure 27). For the construction of this skeleton, two strategies can be employed—using other amino acids and amide coupling agents [150,151] and using chloroacetyl chloride and alkyl-amide [152,153,154,155].
Some biological applications for these diketopiperazines are the antitumor activity of 45 and 46 [154,155] and an FDA-approved drug, Tadalafil, that is used for erectile dysfunction [156].

4. Conclusions

The versatile use of histidine and tryptophan for building simple to complex fused heterocyclic framework can be verified in this review. Tryptophan is more extensively explored than histidine in this field. However, the similar chemical reactivity of these two heteroaromatic amino acids provides comparable skeleton and biological application, where the anti-infective and antitumor activity stands out (Supplementary Materials). The most common reaction involves the Pictet–Spengler reaction, and the influence of natural products in the development of synthetic strategies is notable. Despite the explored synthetic strategies, few studies investigate the biological activity of histidine and tryptophan derivatives, which indicates an opening for future directions in research on drug discovery. Lastly, it is possible to see the potential application of these two heteroaromatic amino acids in the drug development process since it calls for cheap and widely available starting material to prepare drug candidates.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/org6020023/s1, Table with biological activity data for the compounds cited in the manuscript.

Author Contributions

F.F. performed the study design. I.A.S.d.B., J.B.P., A.R.J. and F.F. contributed to the acquisition and analysis of the data. Writing and critical review were performed by I.A.S.d.B., A.R.J. and F.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received funding from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) through scholarships for de Borba, I.A.S. and Peripolli, J.B. Also, this work was financially supported by FAPERGS [Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul] (Grant number 19/2551-0001273-0).

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding author(s).

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ADPAdenosine diphosphate
AhRAryl hydrocarbon receptor
BQ1,4-benzoquinone
CDI1,1′-Carbonyldiimidazole
CNPqConselho Nacional de Desenvolvimento Científico e Tecnológico
DBN1,5-diazabicyclo [4.3.0]non-5-ene
DCE1,2-Dichloroethane
DCMDichloromethane
DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
DKMDiketomorpholines
DKPDiketopiperazines
DMADDimethyl acetylenedicarboxylate
DMDODimethyldioxirane
DMFN,N-Dimethylformamide
DMPDess–Martin periodinane
DMSODimethyl Sulfoxide
FAPERGSFundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
FDAFood and Drug Administration
GBGardenia blue
GCRGlutathione recovery capacity
HDACHistone deacetylase
HIVHuman Immunodeficiency Viruses
HSVHerpes simplex virus
IBDIodobenzene diacetate
IBX2-Iodoxybenzoic acid
JAKJanus kinase
NBSN-Bromosuccinimide
NCSN-Chlorosuccinimide
PCProstate cancer
PDE5Phosphodiesterase type 5
PGProtecting group
PPSETrimethylsilyl polyphosphate
PTSAp-toluene sulfonic acid
PyPyridine
RAFRapidly Accelerated Fibrosarcoma
SSAOSemicarbazide-sensitive amine oxidase
TBDPStert-butyldiphenylsilyl
TCCATrichloroisocyanuric acid
TFATrifluoroacetic acid
TFAETrifluoroacetaldehyde ethyl hemiacetal
TfOHTrifluoromethanesulfonic acid
THFTetrahydrofuran
TMVTobacco Mosaic Virus
Ugi-3CRUgi-three-component reaction

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Figure 1. Representative examples of alkaloids from histidine and tryptophan.
Figure 1. Representative examples of alkaloids from histidine and tryptophan.
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Figure 2. Histidine heterocyclization at imidazole C-4. Conditions: (A) R1 = H and R2 = H: formaldehyde, HCl, 1–12 h [25,26,30,32]. (B) R1 = Me and R2 = benzo [1,3]dioxole: aldehyde, pyridine, 100 °C, N2, 4 h [27] (C) R1 = H and R2 = alkyl or aryl: R1CHO, NaOH, KOH or K2CO3, MeOH or EtOH, reflux, 2–24 h [28,29,30].; (D) R1 = H and R2 = CF3: TFAE, H2O, Ar, 100 °C, 6 h [31].
Figure 2. Histidine heterocyclization at imidazole C-4. Conditions: (A) R1 = H and R2 = H: formaldehyde, HCl, 1–12 h [25,26,30,32]. (B) R1 = Me and R2 = benzo [1,3]dioxole: aldehyde, pyridine, 100 °C, N2, 4 h [27] (C) R1 = H and R2 = alkyl or aryl: R1CHO, NaOH, KOH or K2CO3, MeOH or EtOH, reflux, 2–24 h [28,29,30].; (D) R1 = H and R2 = CF3: TFAE, H2O, Ar, 100 °C, 6 h [31].
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Figure 3. Selective imidazole nitrogen alkylation via heterocyclization protection with CDI. Conditions: (A) CDI, DMF, 60 °C, 3–5 h and (B) (1) R-I, MeCN, reflux, 24 h and (2) HCl, reflux, 12–24 h [34,35].
Figure 3. Selective imidazole nitrogen alkylation via heterocyclization protection with CDI. Conditions: (A) CDI, DMF, 60 °C, 3–5 h and (B) (1) R-I, MeCN, reflux, 24 h and (2) HCl, reflux, 12–24 h [34,35].
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Figure 4. Tetrahydro-imidazo [4,5-c]pyridine core dehydrogenation. Conditions: (A) R1 = Me, R2 = H or aryl and R3 = H: SeO2, AcOH, reflux, 15 min [30]; (B) R1 = H, R2 = Aryl and R3 = H: S, DMF, 120–150 °C, 2–7 h [37,38]; (C) R1 = H, R2 = Aryl and R3 = H: IBX, DMSO, 45 °C, 5–10 h [29]; (D) S8, DMF, 140 °C, 5–20 h [29]; (E) R1 = Me, R2 = H and R3 = CO2Me: SeO2, PPSE, Et3N, CCl4, reflux, 12 h [25,26].
Figure 4. Tetrahydro-imidazo [4,5-c]pyridine core dehydrogenation. Conditions: (A) R1 = Me, R2 = H or aryl and R3 = H: SeO2, AcOH, reflux, 15 min [30]; (B) R1 = H, R2 = Aryl and R3 = H: S, DMF, 120–150 °C, 2–7 h [37,38]; (C) R1 = H, R2 = Aryl and R3 = H: IBX, DMSO, 45 °C, 5–10 h [29]; (D) S8, DMF, 140 °C, 5–20 h [29]; (E) R1 = Me, R2 = H and R3 = CO2Me: SeO2, PPSE, Et3N, CCl4, reflux, 12 h [25,26].
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Figure 5. Histidine reactivity with monosaccharides. Conditions: (A) R = H, 1 M phosphate buffer (pH 5.8), 150 °C, 1 h; (B) R = Me, Oxalic acid DMSO, 60 °C for 30 min, 90 °C for 30 min and 120 °C for 30 min [40,41,42].
Figure 5. Histidine reactivity with monosaccharides. Conditions: (A) R = H, 1 M phosphate buffer (pH 5.8), 150 °C, 1 h; (B) R = Me, Oxalic acid DMSO, 60 °C for 30 min, 90 °C for 30 min and 120 °C for 30 min [40,41,42].
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Figure 6. Selected bioactive compounds prepared with fused heterocyclic scaffolds from histidine.
Figure 6. Selected bioactive compounds prepared with fused heterocyclic scaffolds from histidine.
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Figure 7. 5-6-5-fused ring system prepared from tetrahydro-imidazo [4,5-c]pyridine core. Condition: C2H3NCO, Et3N, DMF, 60 °C, 24 h [45].
Figure 7. 5-6-5-fused ring system prepared from tetrahydro-imidazo [4,5-c]pyridine core. Condition: C2H3NCO, Et3N, DMF, 60 °C, 24 h [45].
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Figure 8. 5-6-6-fused ring system prepared from tetrahydro-imidazo [4,5-c]pyridine core. Conditions: (1) ClCOCH2Cl, Et3N, THF, 0 °C–r.t., 1 h, (2) Aq MeNH2, THF, 45 °C, 45 min [27].
Figure 8. 5-6-6-fused ring system prepared from tetrahydro-imidazo [4,5-c]pyridine core. Conditions: (1) ClCOCH2Cl, Et3N, THF, 0 °C–r.t., 1 h, (2) Aq MeNH2, THF, 45 °C, 45 min [27].
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Figure 9. Imidazo [4,5-a]quinolizine-like 5-6-6-fused ring system from histidine. Conditions: Toluene, 80 °C, 2 h, TFA [47].
Figure 9. Imidazo [4,5-a]quinolizine-like 5-6-6-fused ring system from histidine. Conditions: Toluene, 80 °C, 2 h, TFA [47].
Organics 06 00023 g009
Organics 06 00023 g010
Figure 10. Histidine reactivity with Genipin. Conditions: PBS buffer (pH = 7.35), 32 °C, 55 h [49,50].
Figure 10. Histidine reactivity with Genipin. Conditions: PBS buffer (pH = 7.35), 32 °C, 55 h [49,50].
Organics 06 00023 g010
Organics 06 00023 g011
Figure 11. Hexacyclic bearing diketopiperazine fused ring system binding tryptophan to histidine. Conditions: (1) DEPBT, THF, r.t., (2) HCl/EtOAc (4M), 0 °C, 4 h [51].
Figure 11. Hexacyclic bearing diketopiperazine fused ring system binding tryptophan to histidine. Conditions: (1) DEPBT, THF, r.t., (2) HCl/EtOAc (4M), 0 °C, 4 h [51].
Organics 06 00023 g011
Organics 06 00023 g012
Figure 12. Pictet–Spengler-like reaction with tryptophan. Conditions: (general acid condition): R-CHO, glacial acetic acid or sulfuric acid or PTSA/Toluene or TFA, rt–reflux 1–16 h; (general basic condition): R-CHO, NaOH/water, rt, 2–3 h [57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76].
Figure 12. Pictet–Spengler-like reaction with tryptophan. Conditions: (general acid condition): R-CHO, glacial acetic acid or sulfuric acid or PTSA/Toluene or TFA, rt–reflux 1–16 h; (general basic condition): R-CHO, NaOH/water, rt, 2–3 h [57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76].
Organics 06 00023 g012
Organics 06 00023 g015
Figure 15. Synthesis of β-carboline alkaloids from tryptophan and a second amino acid. Conditions: I2, TFA,DMSO, 120 °C, 24 h [115].
Figure 15. Synthesis of β-carboline alkaloids from tryptophan and a second amino acid. Conditions: I2, TFA,DMSO, 120 °C, 24 h [115].
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Organics 06 00023 g016
Figure 16. Select bioactive compounds prepared using pyrido [3,4-b]indole core from tryptophan.
Figure 16. Select bioactive compounds prepared using pyrido [3,4-b]indole core from tryptophan.
Organics 06 00023 g016
Organics 06 00023 g017
Figure 17. Preparation of hexahydropyrrolo [2,3-b]indole core from tryptophan derivatives. (A) R = Br: NBS, CH3CN or CH2Cl2, 0 °C–rt, 30 min–4 h [119,120]; (B) R = Cl: ZnCl2, PhI(OAc)2, CH3CN, rt, 2 h [121].
Figure 17. Preparation of hexahydropyrrolo [2,3-b]indole core from tryptophan derivatives. (A) R = Br: NBS, CH3CN or CH2Cl2, 0 °C–rt, 30 min–4 h [119,120]; (B) R = Cl: ZnCl2, PhI(OAc)2, CH3CN, rt, 2 h [121].
Organics 06 00023 g017
Organics 06 00023 g018
Figure 18. Preparation of Azepino [4,5-b]indoles. Conditions: (1) K2CO3, DMF, rt, 1–2 h; (2) TfOH, DCE, rt, 2 h [124].
Figure 18. Preparation of Azepino [4,5-b]indoles. Conditions: (1) K2CO3, DMF, rt, 1–2 h; (2) TfOH, DCE, rt, 2 h [124].
Organics 06 00023 g018
Organics 06 00023 g019
Figure 19. Synthesis of 1-Carbamoyl-4-aminoindoloazepinone derivatives via the Ugi reaction. Conditions: MeOH, 70 °C, 48 h [126].
Figure 19. Synthesis of 1-Carbamoyl-4-aminoindoloazepinone derivatives via the Ugi reaction. Conditions: MeOH, 70 °C, 48 h [126].
Organics 06 00023 g019
Organics 06 00023 g020
Figure 20. Synthetic strategy for obtention of the 1,3,4,5-tetrahydrobenzo [cd]indole scaffold. Conditions: Pd(OAc)2, Mo(CO)5, AgOAc, BQ, 1,4-dioxane, Ar, 110 °C, 18 h [129].
Figure 20. Synthetic strategy for obtention of the 1,3,4,5-tetrahydrobenzo [cd]indole scaffold. Conditions: Pd(OAc)2, Mo(CO)5, AgOAc, BQ, 1,4-dioxane, Ar, 110 °C, 18 h [129].
Organics 06 00023 g020
Organics 06 00023 g021
Figure 21. Cyclization step for the diaza-cyclopenta-fluorene-dione core synthesis. Conditions: (1) DMDO, acetone or THF, −78 °C, 1 h; (2) Na2SO3, 0 °C, 1.5 h [132,133].
Figure 21. Cyclization step for the diaza-cyclopenta-fluorene-dione core synthesis. Conditions: (1) DMDO, acetone or THF, −78 °C, 1 h; (2) Na2SO3, 0 °C, 1.5 h [132,133].
Organics 06 00023 g021
Organics 06 00023 g022
Figure 22. Synthetic strategy to give the indolo-quinolino-naphthyridine core. Conditions: (1) p-xylene, reflux, 16 h; (2) n-Bu4NF, THF, r. t., 12 h; (3) DMP, Py, CH2Cl2, 2 days [134].
Figure 22. Synthetic strategy to give the indolo-quinolino-naphthyridine core. Conditions: (1) p-xylene, reflux, 16 h; (2) n-Bu4NF, THF, r. t., 12 h; (3) DMP, Py, CH2Cl2, 2 days [134].
Organics 06 00023 g022
Organics 06 00023 g023
Figure 23. Nocardioazine B and Javanicunines A synthetic pathway and Breviananide E structure [137,138,139].
Figure 23. Nocardioazine B and Javanicunines A synthetic pathway and Breviananide E structure [137,138,139].
Organics 06 00023 g023
Organics 06 00023 g024
Figure 24. Hydantoins and thiohydantoins derivatives from hexahydropyrrolo [2,3-b]indole core. Conditions: Acetone/DMSO, DCM, and MeCN, rt. 2–3 h [54,141,142,143,144,145,146].
Figure 24. Hydantoins and thiohydantoins derivatives from hexahydropyrrolo [2,3-b]indole core. Conditions: Acetone/DMSO, DCM, and MeCN, rt. 2–3 h [54,141,142,143,144,145,146].
Organics 06 00023 g024
Organics 06 00023 g025
Figure 25. Initial cyclization step for the synthesis of (+)-Tabertinggine. Conditions: (1) PTSA, H2O, toluene:THF (2:1), distill; (2) THF, reflux, 24 h [147].
Figure 25. Initial cyclization step for the synthesis of (+)-Tabertinggine. Conditions: (1) PTSA, H2O, toluene:THF (2:1), distill; (2) THF, reflux, 24 h [147].
Organics 06 00023 g025
Organics 06 00023 g026
Figure 26. Five-membered heteroaromatic ring fused to tetrahydro-β-carboline and β-carboline. Conditions: (A) DMAD, Ac2O, 70 °C, 2 h; (B) MeOH or EtOH, 80–90 °C, 2–4 h; (C) DMSO/DMF, Et3N, S8, 120–150 °C, 2–4 h [148,149].
Figure 26. Five-membered heteroaromatic ring fused to tetrahydro-β-carboline and β-carboline. Conditions: (A) DMAD, Ac2O, 70 °C, 2 h; (B) MeOH or EtOH, 80–90 °C, 2–4 h; (C) DMSO/DMF, Et3N, S8, 120–150 °C, 2–4 h [148,149].
Organics 06 00023 g026
Organics 06 00023 g027
Figure 27. Diketopiperazine-fused to tetrahydro-β-carboline core building and representative biological application examples. Conditions: (A) amide coupling followed by base addition (NH4OH or N-methylmorpholine), rt; (B) (1) Et3N or NaHCO3, DCM, rt, 2 h; (2) MeOH, 70 °C, 16 h [150,151,152,153,154,155,156].
Figure 27. Diketopiperazine-fused to tetrahydro-β-carboline core building and representative biological application examples. Conditions: (A) amide coupling followed by base addition (NH4OH or N-methylmorpholine), rt; (B) (1) Et3N or NaHCO3, DCM, rt, 2 h; (2) MeOH, 70 °C, 16 h [150,151,152,153,154,155,156].
Organics 06 00023 g027
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MDPI and ACS Style

de Borba, I.A.S.; Peripolli, J.B.; Joaquim, A.R.; Fumagalli, F. Beyond Peptides and Peptidomimetics: Natural Heteroaromatic Amino Acids in the Synthesis of Fused Heterocyclic Frameworks for Bioactive Agents. Organics 2025, 6, 23. https://doi.org/10.3390/org6020023

AMA Style

de Borba IAS, Peripolli JB, Joaquim AR, Fumagalli F. Beyond Peptides and Peptidomimetics: Natural Heteroaromatic Amino Acids in the Synthesis of Fused Heterocyclic Frameworks for Bioactive Agents. Organics. 2025; 6(2):23. https://doi.org/10.3390/org6020023

Chicago/Turabian Style

de Borba, Isis Apolo Silveira, Jamile Buligon Peripolli, Angélica Rocha Joaquim, and Fernando Fumagalli. 2025. "Beyond Peptides and Peptidomimetics: Natural Heteroaromatic Amino Acids in the Synthesis of Fused Heterocyclic Frameworks for Bioactive Agents" Organics 6, no. 2: 23. https://doi.org/10.3390/org6020023

APA Style

de Borba, I. A. S., Peripolli, J. B., Joaquim, A. R., & Fumagalli, F. (2025). Beyond Peptides and Peptidomimetics: Natural Heteroaromatic Amino Acids in the Synthesis of Fused Heterocyclic Frameworks for Bioactive Agents. Organics, 6(2), 23. https://doi.org/10.3390/org6020023

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