Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• ) [100][101]. In this chapter, a few other examples are discussed. Malaria is one of the most widespread diseases that still poses a severe threat to inhabitants and travelers of tropical regions within Africa, Asia, and Latin America. Uncomplicated cases, caused by Plasmodium parasites, are usually

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

• Kah Yean Lum,
• Jonathan M. White,
• Daniel J. G. Johnson,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2023, 19, 107–114, doi:10.3762/bjoc.19.11

• , Australia Discovery Biology, Griffith University, Nathan, QLD 4111, Australia NatureBank, Griffith University, Nathan, QLD 4111, Australia 10.3762/bjoc.19.11 Abstract Nine new fluorinated analogues were synthesised by late-stage functionalisation using Diversinate™ chemistry on the Open Source Malaria (OSM

• ) triazolopyrazine scaffold (Series 4). The structures of all analogues were fully characterised by NMR, UV and MS data analysis; three triazolopyrazines were confirmed by X-ray crystal structure analysis. The inhibitory activity of all compounds against the growth of the malaria parasite Plasmodium falciparum (3D7

• ; triazolopyrazine; scaffold; Open Source Malaria; Introduction Malaria is an infectious disease caused by Plasmodium parasites and is a major global threat to human health. The WHO World Malaria Report 2021, estimates 241 million cases of malaria and 627,000 deaths globally in 2020, an increase of 12% from the

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• of antivirals which solely target the dengue virus via the inhibition of an essential interaction between the viral proteins NS3 and NS4B [200]. Still in the domain of infectious diseases, there are two very advanced public-based endeavors aiming at providing drugs against malaria which are

• chemical libraries. With a very different starting point but also on the malaria front, the remarkable ozonides OZ277/arterolane (41) [210][211] and OZ439/artefenomel (42) [212][213][214] stemmed from academic collaborations across the world which started in 2000. While arterolane (41) is a drug used in

• combination with piperaquine (Synriam), the analog artefenomel (42) is undergoing clinical trials, including in combination with DSM-265 (39) [215][216][217][218]. Of note is that prior to 1971, thinking of developing a peroxide-containing compound for a clinical use against malaria would have not been

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• , natural and (semi)synthetic endoperoxides with wide structural diversity show antimalarial activity against Plasmodium falciparum malaria. In this case, the reductive activation of the endoperoxide ring with the homolytic cleavage of the O–O bond leads to the generation of carbon-centered free radicals

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• cycle from 3-methyl-2-(2,3,3-trichloro-1-nitroallylidene)oxazolidine (6) is also described. In addition, the antimalarial activity of the synthesized compounds has been evaluated in vitro against the protozoan malaria parasite Plasmodium falciparum. Notably, the 7-chloro-4-(5-(dichloromethyl)-4-nitro-3

• ; Introduction Tropical malaria remains one of the most devastating human diseases with over half of the world’s population being at risk of infection. In 2019, there were 229 million cases of malaria worldwide resulting in an estimated 409,000 fatalities [1]. Chloroquine has been utilized extensively for

• decades because of its efficacy, safety, and low cost. However, the widespread resistance of Plasmodium falciparum to chloroquine has hampered efforts to combat malaria [2] resulting in artemisinin-based combination therapies as currently recommended standard. Notably, the use of chloroquine

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• , three drugs are highlighted that continue to be used in medical practice. Atovaquone (12) is a drug that targets the elimination of the parasite Plasmodium spp. which is the etiological agent of malaria [28][29]. According to data from the World Health Organization (WHO), in 2018, there were

• approximately 228 million cases of malaria worldwide, with the majority of cases in Africa. It is a serious illness that can lead to death if not treated immediately. This medication has therapeutic use for the treatment or prevention of mild cases of Plasmodium vivae infection. Two other drugs structurally

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• achieved by solid-state synthesis. Our synthetic strategy could synthesize the target peptide in high yield with good purity Keywords: antimalarial; highly methylated polypeptides; hoshinoamides; total synthesis; Introduction Malaria is an insect-borne infectious disease caused by parasites of the genus

• Plasmodium, which seriously threatens human life and health [1]. Half of the world's population is at the risk of malaria, causing 200 million new infections and killing hundreds of thousands of people each year [2]. Current medicines for malaria include quinolone [3][4], folic acid antagonist [5][6] and

• of the malaria parasites (IC50 = 0.96 μM) and African sleeping sickness (IC50 = 2.9 μM). Hoshinoamide C was firstly synthesized from Boc-protected amino acids in liquid phase [12]. Both hoshinoamides A and B are highly methylated polypeptides containing three N-methyl amino acids: N-Me-ʟ-Leu7, N-Me-ᴅ

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• ], asthma and malaria (southern Sahara) [2][3], and to combat intestinal parasites (Bolivia) [5]. In addition, this plant has also been used as a natural pesticide, particularly in cereal conservations, and to repel mosquitoes (southern Sahara) [2][3]. Biological activity investigations of the plant extract

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

• against different types of diseases, such as cancer [1][2], malaria [3][4], Chagas disease [5][6], HIV [7][8], depression [9][10], amnesia [11], Alzheimer [12], and maybe even in a more recent scenario, COVID-19 [13]. Even though many compounds are found to present activity against these diseases, only a

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• and antiangiogenic properties have been attributed to fumagillin [129][136][137][138][139][140]. Specific antibiotic activities were demonstrated against the pathogen Entamoeba histolytica and later against eukaryotic parasites such as Trypanosoma and Plasmodium the causative agent of malaria [141

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

• treatment installations [2]. In addition, artemisinin, which is a drug to treat malaria, was produced in an industrial-scale photoreactor in a Sanofi production facility in Italy [3]. Furthermore, the production of some fine chemicals, such as ε-caprolactam, rose oxide, and vitamin D on an industrial scale

Anthelmintic drug discovery: target identification, screening methods and the role of open science

• Frederick A. Partridge,
• Ruth Forman,
• Carole J. R. Bataille,
• Graham M. Wynne,
• Marina Nick,
• Angela J. Russell,
• Kathryn J. Else and
• David B. Sattelle

Beilstein J. Org. Chem. 2020, 16, 1203–1224, doi:10.3762/bjoc.16.105

• the Medicines for Malaria Venture Pathogen Box, have been successful at facilitating screening in diverse assays against many different parasite pathogens and models. Of the compounds identified so far in these screens, tolfenpyrad, a repurposed insecticide, shows significant promise and there has

• infections is sparse. This contrasts with the situation for malaria and kinetoplastid infections, where efforts, particularly by the Drug for Neglected Diseases Initiative and Medicines for Malaria Venture, in partnership with various pharmaceutical companies, are now paying off with an improved pipeline of

• partnership between Medicines for Malaria Venture and GSK developed tafenoquine (11), which is effective as a single-dose treatment for the radical cure of Plasmodium vivax malaria [68]. While neither of these examples is for helminth infection, they show that these organisational models can be successful at

Opening up connectivity between documents, structures and bioactivity

• Christopher Southan

Beilstein J. Org. Chem. 2020, 16, 596–606, doi:10.3762/bjoc.16.54

• rather than a primary activity report) this example had an important sequel. During the curation of the new Guide to Malaria Pharmacology 14 of the 16 compounds now have full DARCLP annotation where D is the primary activity report, P is the Plasmodium target and activity values against the parasite are

Terpenes

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 2966–2967, doi:10.3762/bjoc.15.292

• taxol from Taxus brevifolia that is used to treat breast and other types of solid cancers, while artemisinin from Artemisia annua is used as a cure against malaria [4]. This thematic issue covers all different aspects of terpene chemistry and biochemistry, including compound isolation and structure

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• Abstract Terpenoids are the largest and structurally most diverse class of natural products. They possess potent and specific biological activity in multiple assays and against diseases, including cancer and malaria as notable examples. Although the number of characterized terpenoid molecules is huge, our

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• ]. Interestingly, the β-CBT derivative missing the hydroxy group at C6 called thunbergol (18, Scheme 3), already inhibited the growth of two parasites Trypanosoma brucei rhodesiense, causing African sleeping sickness, as well as Plasmodium falciparum causing Malaria tropica, while having only minor human

One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

• Christina Görgen,
• Katharina Boden,
• Guido J. Reiss,
• Walter Frank and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1360–1370, doi:10.3762/bjoc.15.136

• shown nanomolar in vitro activities against chloroquine-sensitive and resistant strains of Plasmodium falciparum and can therefore be considered for the treatment of malaria [21]. Furthermore, similar derivatives have shown micromolar and submicromolar activity against 60 selected cancer cell lines

Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin

• Toni Smeilus,
• Farnoush Mousavizadeh,
• Johannes Krieger,
• Xingzhao Tu,
• Marcel Kaiser and
• Athanassios Giannis

Beilstein J. Org. Chem. 2019, 15, 567–570, doi:10.3762/bjoc.15.51

• not show any toxicity against L6 cells (a primary cell line derived from rat skeletal myoblasts). These results contribute to a better understanding of artemisinins mechanism of action. Keywords: artemisinin; biomimetic synthesis; Diels–Alder reaction; malaria; peroxides; Introduction The isolation

• ]. As artemisinin has poor solubility and bioavailability, several derivatives of this natural product like artesunate and artemether were developed and are currently used in combination with other drugs for the treatment of malaria [4]. However, the exact mechanism of action of this endoperoxide

• application in the treatment of diabetes mellitus. These facts indicate the clinical potential of artemisinins and “it is likely that artemisinin drugs will become a major armamentarium combating a variety of human diseases beyond malaria” [9]. In the past, several semi-synthetic artemisinin derivatives were

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria. Keywords: antimalarial; API manufacturing; flow

• intensification [1][2][3]. In 2016, estimated 212 million cases of malaria, including 429,000 fatalities, were reported worldwide, with the majority of these cases occurring in sub-Saharan Africa and Southern Asia [4]. The malaria epidemic is particularly difficult to control due to the multidrug resistant nature

• of the malaria parasite Plasmodium falciparum. Hydroxychloroquine (1) is an antimalarial drug developed for both treatment and prevention of the disease in response to the widespread malaria resistance to chloroquine (2, Figure 1) [5][6]. Additionally, hydroxychloroquine (1, HCQ) is an effective non

Transition-metal-free [3 + 3] annulation of indol-2-ylmethyl carbanions to nitroarenes. A novel synthesis of indolo[3,2-b]quinolines (quindolines)

• Michał Nowacki and
• Krzysztof Wojciechowski

Beilstein J. Org. Chem. 2018, 14, 194–202, doi:10.3762/bjoc.14.14

• (quindoline) system is present in numerous alkaloids of plant origin representing several biological activities and used in traditional tropical medicine for the treatment of various diseases, particularly malaria [1][2][3][4][5]. Further development revealed the potential of synthetic quindoline derivatives

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• proteases [7], cruzain 20 [8][9], caspases [10] and peptidyl aminopeptidases [11]. These protease inhibitors show potential for the treatment of Chagas disease [2][9], Huntington’s disease [10], malaria [11], autoimmune diseases [6] and the imaging of tumor associated macrophages [2]. Whereas the carboxylic

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• ) and glibenclamide (2), which belong to the class of sulfonylureas, and guanidine-derived metformin (3) are among the top selling oral hypoglycemics globally. Proguanil (4), a biguanide derivative, is widely prescribed to treat malaria, a disease that took over 430 000 lives in 2015 [6]. In the past 20

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• the World Health Organization (WHO) malaria is a widely distributed illness. About 3.2 billion people remain at risk of malaria and in 2015 214 million cases of malaria and 438 thousands deaths from it have been registered [10]. Compounds with high antimalarial [11][12][13][14][15][16][17][18][19][20

• six-membered 1,2-dioxane [40][41][42], 1,2-dioxene [43], 1,2,4-trioxane [22][44][45] cycles. The naturally occuring peroxide artemisinin and its semisynthetic derivatives, artemether, arteether, and artesunate, are applied in large scale for malaria treatment [46][47]. Organic peroxides, their

Reactions of N,3-diarylpropiolamides with arenes under superelectrophilic activation: synthesis of 4,4-diaryl-3,4-dihydroquinolin-2(1H)-ones and their derivatives

• Larisa Yu. Gurskaya,
• Diana S. Belyanskaya,
• Dmitry S. Ryabukhin,
• Denis I. Nilov,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2016, 12, 950–956, doi:10.3762/bjoc.12.93

• very important class of heterocycles, which are used in chemistry, biology, medicine, and materials science. For instance, see a series of recent reviews on anti-malaria drugs containing a quinoline motif in the structure [1][2][3]. The synthesis of quinolines is an important task of organic chemistry