Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• rapid generation of chemical libraries with high diversity in a time-efficient and environmentally sustainable manner. In this review, we focus on central nervous system (CNS) disorders, particularly Alzheimer's disease, Parkinson's disease, schizophrenia, depression, and epilepsy, where MCRs have

• ; schizophrenia; Introduction Multicomponent reactions Due to efforts to develop new drug arsenals faster to overcome the difficulties of medicinal chemistry (multistage and highly wasteful processes), multicomponent reactions (MCRs) have emerged as a plausible solution. MCRs are convergent reactions in which

• illnesses characterized by delusions, hallucinations, and disorganized behavior. This illness can manifest itself across a spectrum of conditions such as major depressive disorder (MDD), bipolar disorder, delusional and schizophreniform disorder. The prototypical psychotic disorder is schizophrenia, which

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• significantly lower potency of 32. Ulotaront (33, SEP-363856) [38] is a phase-3 clinical lead for the treatment of schizophrenia, displaying TAAR1 (trace-amine-associated receptor 1) [39] and 5-HT1A agonism as mode of action, lacking dopamine D2 and 5-HT2A antagonism. SAR exploration of the ulotaront family was

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• interest from the medicinal chemist community, which led to the development of several antidepressant agents such as dibenzepin, sintamil, as well as the well-known medication, clozapine, an FDA-approved atypical antipsychotic drug, that has been adopted as a treatment of schizophrenia and schizoaffective

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• hypertention [5], buspirone for anxiety disorders [6], cevimeline for dry mouth and dry eye syndrome [7], fluspirilene for schizophrenia [8] and ilbesartan for hypertention and diabetic nephropathy [9], to mention a few (Figure 1). Hence the development of novel synthetic methods to construct spirocycles [10

New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• ; Introduction Lumateperone (1) is a recently launched drug marketed for the treatment of schizophrenia and developed for further neuropsychiatric and neurological disorders [1][2][3][4][5][6] (Figure 1). The first synthesis of lumateperone (1, Caplyta®), developed by Intra-Cellular Therapies, was disclosed in

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• addition, the ceramic can enhance the mechanical properties of composite within the cryogel and can be tailored for specific drugs and drug-release profiles [96]. The drug aripiprazole used to treat schizophrenia was recently investigated for delivery using cryogels comprising β-cyclodextrin (β-CD

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

Azologization of serotonin 5-HT₃ receptor antagonists

• Karin Rustler,
• Galyna Maleeva,
• Piotr Bregestovski and
• Burkhard König

Beilstein J. Org. Chem. 2019, 15, 780–788, doi:10.3762/bjoc.15.74

• developmental stages my lead to altered cognitive ability, neurodevelopmental disorders, and increased incidence of psychopathologies such as autism and schizophrenia [15][16]. Serotonin operates via seven classes of 5-HT receptors of which six are G protein-coupled receptors (GPCRs) and only one, the 5-HT3R

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases

• Antonella Petri,
• Valeria Colonna and
• Oreste Piccolo

Beilstein J. Org. Chem. 2019, 15, 60–66, doi:10.3762/bjoc.15.6

• intermediates for the synthesis of a large number of biologically active compounds used for the treatment of obesity, type-I and II diabetes mellitus or as psychotropic drugs against depression and schizophrenia [15][16][17][18][19]. In particular (R)-3-amino-1-Boc-piperidine is a useful precursor of compounds

Synthesis of indole–cycloalkyl[b]pyridine hybrids via a four-component six-step tandem process

• Muthumani Muthu,
• Rakkappan Vishnu Priya,
• Abdulrahman I. Almansour,
• Raju Suresh Kumar and
• Raju Ranjith Kumar

Beilstein J. Org. Chem. 2018, 14, 2907–2915, doi:10.3762/bjoc.14.269

• called superficial basal cell carcinoma (Figure 1) [28][29]. Loratadine is a second-generation histamine H1 receptor antagonist used to treat allergic rhinitis and urticarial [30][31]. Blonanserin is an atypical antipsychotic drug used to treat schizophrenia [32], whereas the decahydrocyclododeca[b

Rhodium-catalyzed C–H functionalization of heteroarenes using indoleBX hypervalent iodine reagents

• Erwann Grenet,
• Ashis Das,
• Paola Caramenti and
• Jérôme Waser

Beilstein J. Org. Chem. 2018, 14, 1208–1214, doi:10.3762/bjoc.14.102

• -pyridinone ring is present in milrinone (1), used to treat heart failure, while a 4-pyridinone is part of mimosine (2), an alkaloid isolated from Mimosa pudica. A benzene-fused pyridinone – a quinolone – can be found in brexpiprazole (3), a drug used against schizophrenia. In addition, the indole core is

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• treat schizophrenia. In an interesting report Aggarwal et al. [74] described the synthesis of 4,7-dihydropyrazolo[3,4-b]pyridine-5-nitriles 92 from the reaction of β-ketonitriles 15 with several aryl/heteroaryl hydrazines 14 in ethanol with a catalytic amount of conc. HNO3 (Scheme 26). The authors

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• pharmaceutical ingredients. The following section will describe a few of such efforts. In 2013, Witt et al. reported a scalable process for the synthesis of GSK3B inhibitor AZD8926, 103 [99]. The drug is therapeutically useful for the treatment of CNS disorder viz. Alzheimer’s disease (AD), Schizophrenia and

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• treatment of bipolar disorder and schizophrenia [10]. The process involves four reaction steps, one inline extraction, and a filtration step. The reaction is shown in Scheme 1. Initially, a Buchwald–Hartwig reaction is carried out between aryl iodide and aminothiazole. Pd2dba3 was used as a catalyst and

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• metabotropic process. There is ongoing interest in mGluRs as drug targets, and the therapeutic potential of mGluR ligands for the treatment of CNS disorders and ailments such as Alzheimer’s and Parkinson’s disease, depression, anxiety, and schizophrenia is being validated [121][122]. The discovery of group II

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

• Beatrice Bechi,
• David Amantini,
• Cristina Tintori,
• Maurizio Botta and
• Romano di Fabio

Beilstein J. Org. Chem. 2014, 10, 1114–1120, doi:10.3762/bjoc.10.110

• -glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson’s and Alzheimer’s and in

• coupled or metabotropic glutamate receptors (mGluRs) [6][7]. To date, eight different metabotropic receptor subtypes (mGluR1–8) have been identified. Compounds that modulate the function of the mGluRs might be useful for treating a wide range of CNS disorders including schizophrenia, depression, anxiety

Synthesis of indole-based propellane derivatives via Weiss–Cook condensation, Fischer indole cyclization, and ring-closing metathesis as key steps

• Sambasivarao Kotha,
• Ajay Kumar Chinnam and
• Arti Tiwari

Beilstein J. Org. Chem. 2013, 9, 2709–2714, doi:10.3762/bjoc.9.307

• potential drugs for the treatment of schizophrenia and alcohol addiction [34]. However, the synthesis of indole alkaloid derivatives containing a propellane ring system is a challenging task due to the presence of quaternary centers involved with these systems [35]. We envisioned a new synthetic route to

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• dopaminergic neurotransmission. This knowledge will be useful in developing novel central nervous system (CNS) drugs to treat conditions in which the dopamine receptors are directly implicated (i.e., Parkinson’s disease, schizophrenia, Gilles de la Tourette syndrome, etc.) [59][60][61]. Within the context of G

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

Identification and synthesis of impurities formed during sertindole preparation

• I. V. Sunil Kumar,
• G. S. R. Anjaneyulu and
• V. Hima Bindu

Beilstein J. Org. Chem. 2011, 7, 29–33, doi:10.3762/bjoc.7.5

• atypical anti-psychotic drug is used for the treatment of schizophrenia. During the laboratory optimization and later during its bulk synthesis the formation of various impurities was observed. The impurities formed were monitored and their structures were tentatively assigned on the basis of their

• cognitive disorders. It has been reported to show antipsychotic effect in clinical studies. In contrast to other antipsychotics, sertindole has no associated sedative effects; sedation may add to the cognitive problems inherent in schizophrenia. Sertindole is designated chemically as 1-[2-[4-[5-chloro-1-(4

Flexible synthesis of poison- frog alkaloids of the 5,8-disubstituted indolizidine- class. II: Synthesis of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors

• Soushi Kobayashi,
• Naoki Toyooka,
• Dejun Zhou,
• Hiroshi Tsuneki,
• Tsutomu Wada,
• Toshiyasu Sasaoka,
• Hideki Sakai,
• Hideo Nemoto,
• H. Martin Garraffo,
• Thomas F. Spande and
• John W. Daly

Beilstein J. Org. Chem. 2007, 3, No. 30, doi:10.1186/1860-5397-3-30

• . [5] Nicotinic receptors have been implicated in a wide range of neuronal dysfunctions and mental illness, such as epilepsy, Tourette's syndrome, Alzheimer's disease, Parkinson's disease, and schizophrenia. [5][6] Since different subtypes of nicotinic receptors are involved in different neurological

• , learning and memory. [5][6] Some ligand-binding and autoradiography studies with postmortem human brain suggest that loss of neuronal nicotinic receptors is related to central cholinergic disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia. [4][6] For instance, in schizophrenic

• patients, decrease in binding of α-bungarotoxin (α-Bgt), a major specific ligand for α7 nicotinic receptors, has been detected in hippocampus, thalamus and frontal cortex [16][17]. Therefore, loss of α7 nicotinic ligand-binding appears to be an early presymptomatic diagnostic marker for schizophrenia. For