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β- Carbolines
SCHEME 2.11 Preparation of bromide salts of β- carbolines.
SCHEME 2.12 Coupling approach for the synthesis of β- carboline derivatives.
condensing the derivative of carboline carboxylic acid with amino- containing
neamine derivatives at room temperature under acidic conditions. Carboxylic
acids are insoluble in carboline, so the coupling reaction was performed in a DMF
(Dimethylformamide) solution. N,N- diisopropylethylamine (DIPEA) greatly
facilitated product purication by promoting efcient amide- bond formation when
combined with HOBT (hydroxybenzotriazole) and TBTU (2- (1H- benzotriazole- 1-
yl)- 1,1,3,3- tetramethylaminium tetrauoroborate). The reaction was also concluded
rapidly after DIPEA addition was completed. The desired compounds were obtained
after being saponied with sodium methoxide in methanol and subsequently reduced
with hydrogen sulphide (Wu et al. 2010).
The general approach to synthesizing new 1,2,3- triazole- ringed β- carboline
derivatives is depicted in Scheme 2.13 (Salehi et al. 2016). L- tryptophan methyl ester
and O- propargylated benzaldehydes underwent a Pictet- Spengler reaction, which
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β- Carbolines as Antibacterial Agents
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SCHEME 2.13 Routes for the synthesis of 1,2,3,4- tetrahydro- β- carboline compounds.
SCHEME 2.14 Stereoselective synthesis of tetrahydro- β- carboline diketopiperazines.
produced a racemic mixture of tetrahydro- carboline compounds. Researchers looked
into using sulphur, KMnO4, and IBX as oxidizing reagents to transform 1,2,3,4-
tetrahydro- carboline derivatives into their β- carboline counterparts. Other derivatives
were oxidized using the same technique.
From L- tryptophan methyl ester hydrochloride and aldehydes, single isomers of
tetrahydro- carboline diketopiperazines were made using a four- step reaction that
included the Pictet- Spengler reaction, crystallization- induced asymmetric transformations (CIAT), the Schotten- Baumann reaction, and intramolecular ester amidation
(Scheme 2.14) (Ma et al.2013).
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β- Carbolines
SCHEME 2.15 Synthesis of β- carboline dimers and their N2- alkylated analogues.
SCHEME 2.16 Synthesis of β- carboline dimers via Oxidative approach.
The biological effects of beta- carbolines, a class of indole alkaloids, are quite varied.
The purpose of this research was to determine the structural basis for the inhibitory
effects of β- carboline derivatives in vitro against pathogenic microorganisms of clinical
signicance. Therefore, a number of β- carboline dimers and N2- alkylated analogues
were synthesized and tested for antibacterial activity. Dimeric 6- chlorocarboline N2-
benzylated salt showed strong activity against S. aureus at MICs of 0.010.05 mol/ mL.
Our results demonstrate that N1N1- dimerization and N2- benzylation signicantly elevate compounds’ antimicrobial activities (Scheme 2.15 & 2.16) (Suzuki et al. 2018).
Schema 2.17 shows the steps needed to synthesize β- carboline- oxazol- 5- ones.
The technique developed by the Savariz group was applied to create substituted β-
carboline- 3- carboxylic acids using commercial L- tryptophan. Analogs of tetrahydro-
carbolines were produced by Pictet- Spengler condensation of L- tryptophan methyl
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β- Carbolines as Antibacterial Agents
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SCHEME 2.17 Synthesis of β- carboline derivatives using L- tryptophan.
ester with benzaldehyde, 4- methoxybenzaldehyde, and 4- hydroxybenzaldehyde. The
β- carboline- 4H- oxazol- 5 ones were made by the Erlenmeyer Plöchl reaction, which is
the most widely used technique for producing oxazolones. Analogues of β- carboline- 3-
carboxylic acids were created by activating β- carboline- 3- carboxylic acids in pyridine
with DMAP (dimethylaminopyridine) and DCC (N,N’- dicyclohexylcarbodiimide),
and then treating the resultant solution with glycine ethyl ester hydrochloride (Savariz
et al. 2012).
In order to investigate new antibacterial frameworks and assess antiphytopathogen
efcacy in vitro and in vivo, the author synthesized a number of unique THC
derivatives. Target compounds showed excellent action against three rogue
phytopathogens, namely X. axonopodis pv. citri, P. syringae pv. actinidiae (Psa), and
X. oryzae pv. oryzae, as evidenced by their respective EC50 values of 2.06 (I23),
2.39 (II9), and 1.69. These results were superior to those seen with 1,2,3,4- THC, the
parent structure, and with the control group. In vivo tests showed that at 200 g/ mL,
they are highly effective at preventing the spread of both rice bacterial blight and
kiwifruit (Scheme 2.18) (Liu et al. 2020).
To produce new beta- carboline derivatives, a six- step reaction procedure was
used (Scheme 2.19). Initially, L- amine tryptophan’s group was shielded with BOC
anhydride, and subsequent spectroscopic analyses veried the product’s structure.
The next step involved esterifying the carboxyl group of BOC tryptophan with 10-
undecenol. The esteried product was deprotected using acid to yield a free amine.
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β- Carbolines
SCHEME 2.18 Synthesis of tetrahydro- β- carboline derivatives via epoxide ring opening.
SCHEME 2.19 Synthesis of substituted β- carboline derivatives using L- tryptophan.
Following that, the amino group was condensed with various types of aldehydes to
produce Schiff bases. Then, the resulting products were made by cyclizing Schiff
bases (Kontham et al. 2021).
Scheme 2.20 depicts the process for creating maleimide, phthalimide, and
succinimide- substituted phenylimide- β- carboline derivatives, as described by Ortiz
et al (Lopes- Ortiz et al. 2020). Compound precursors were obtained via the Pictet-
Spengler reaction of L- tryptophan methyl ester with aromatic aldehydes containing
electron- donating and electron- withdrawing groups; subsequent xylene oxidation
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β- Carbolines as Antibacterial Agents
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SCHEME 2.20 Different approaches for the synthesis of β- carbolines.
of THC obtained with sulphur yielded the corresponding methyl β- carboline- 3-
carboxylates. By reacting carbohydrazides with phthalic anhydride, β- carboline- 3-
N- (1,3- dioxo- 1,3- dihydro- isoindol- 2- yl)- carboxamides were formed. The phenyl
and 4- uorophenyl groups at position 1 of the β- carboline nucleus were prepared
by treating the carbohydrazide with maleic anhydride in acetic acid and anhydrous
sodium acetate, respectively. An initial attempt to synthesize β- carboline- 3-
N- (2,5- dioxo- pyrrolidin- 1- yl)- carboxamides by reacting carbohydrazides with
succinic anhydride under anhydrous toluene reux is described by Brosse et al. All
carbohydrazides, however, were only found to generate noncyclized intermediates
under these conditions. The nal compound was synthesized by reacting the appropriate starting carbohydrazides with succinic anhydride in the presence of a catalytic
amount of p- toluene sulfonic acid (Brosse et al. 2003).
3.7 APPLICATIONS OF Β- CARBOLINES
The effects of natural beta- carbolines are primarily neurological, but they may
also have antioxidant effects (Liao et al. 2020). Recently, β- carbolines derivatives
developed in a laboratory have been shown to have neuroprotective (Gulyaeva and
Aniol 2012), cognitive enhancing, and anticancer properties (Aaghaz et al. 2021).
Amazonian peoples used a hallucinogen made from the liana Banisteriopsis caapi,
which was rst described as such in the middle of the nineteenth century. In the early
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twentieth century, European pharmacists discovered that harmine was an active ingredient (Djamshidian et al. 2016). Interest in this nding’s therapeutic potential has
β- Carbolines
prompted additional study. Harmine’s pharmacological effects can be traced back to
its ability to inhibit monoamine oxidase (MAO). Banisteriopsis caapi and Peganum
harmala extracts have been shown to trigger dopamine release in the striatum in both
in vitro and in vivo rodent studies, respectively (Samoylenko et al. 2010; Schwarz
et al. 2003). Moreover, in mice treated with MPTP (1- methyl- 4- phenyl- 1,2,3,6tetrahydropyridine), harmine increases the number of viable dopaminergic neurons
(Barallobre et al. 2014).
3.8 CONCLUSION
β- carbolines are a signicant group of nitrogen- containing heterocycles because of
their wide range of biological and pharmaceutical uses. There is a wide range of therapeutic applications for the β- carboline family of heterocyclic natural products. Due
to their value, many scientists have already made contributions to the bioactivity and
preparation of these intriguing frameworks. The antibacterial properties and overall
structure of β- carbolines skeletons have been discussed in this chapter. This chapter
provided a detailed discussion, supported by examples, of the nature and prevalence
of β- carbolines frameworks. We also described the origins, structures, properties,
and potential bioactivities of several naturally occurring products with a β- carbolines
skeleton. In addition, the synthetic aspect and several important applications were
covered.
ACKNOWLEDGMENTS
The authors are thankful to the Department of Applied Chemistry, Amity School of
Engineering & Technology (ASET), Gwalior, for all the necessary facilities.
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