Design, synthesis, and biological evaluation of FXR/ASK1 dual-target modulators

• Xi Zhang,
• Jingyan Wang,
• Ziqiang Zhao,
• Caiyi Wang,
• Zenghui Ye,
• Wei-Yuan Ma,
• Jian-Xing Xu and
• Fengzhi Zhang

Beilstein J. Org. Chem. 2026, 22, 771–781, doi:10.3762/bjoc.22.59

• desired outcomes, recent research has shifted towards investigating the potential of dual FXR agonists. A number of dual-targeting drugs, which engage FXR in conjunction with other pathways, have demonstrated considerable potential in enhancing the efficacy of MASH treatment outcomes [11][12] (Scheme 1

• . Given its central role, there are several dual-target drugs being developed that inhibit ASK1 alongside other pathways as antifibrotic agents for MASH treatment [16][17]. ASK1 activation has been demonstrated to drive key pathological processes in the liver, including hepatocyte dysfunction, apoptosis

• amide of Val 757, and concurrently, a triazole nitrogen engages in a hydrogen bond with the amine moiety of Lys 709 [43]. By merging the key pharmacophores of the two drugs and systematically optimizing the resulting bipharmacophoric structure, we ultimately obtained balanced dual-target modulators

Rongalite addition to dienones: diastereoselectivity in cyclic sulfone synthesis; stereochemical rationalization and prospects as a general conjugate nucleophile

• Melina Goga,
• Hao Zong,
• James Franco,
• Jazmine Prana,
• Rudolph Michel,
• Antonia Muro,
• Elana Rubin,
• Janet Brenya,
• Henk Eshuis and
• Magnus W. P. Bebbington

Beilstein J. Org. Chem. 2026, 22, 742–752, doi:10.3762/bjoc.22.56

• the reactivity of other readily available sulfinate nucleophiles using competition and exchange experiments. Keywords: diastereoselectivity; Rongalite; sulfones; Introduction Sulfonyl groups are widespread in licensed drugs [1]. New methods for the incorporation of sulfonyl groups into organic

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• iminoesters 34 derived from natural compounds or currently available synthetic drugs (Scheme 17). Iminoesters containing molecules of cholesterol, androsterone, indomethacin, pitavastatin, menthol, as well as fructose and glucose, were introduced into the reaction. In [55], copper(I)-catalyzed asymmetric 1,3

Anti-invasive and cytotoxic evaluation of a (+)-pinoresinol-based semisynthetic library against glioblastoma

• Chen Zhang,
• Kah Yean Lum,
• Jonathan M. White,
• Paul I. Forster,
• Nicholas Booth,
• Sunita A. Ramesh and
• Rohan A. Davis

Beilstein J. Org. Chem. 2026, 22, 691–704, doi:10.3762/bjoc.22.54

• ; glioblastoma; (+)-pinoresinol; seeds; semisynthesis; Introduction Since ancient times, natural products have played a crucial role in the development of medicines for various diseases [1][2][3][4]. A recent review by Newman et al. has identified that over the past four decades, >30% of therapeutic drugs

• spectrometric techniques. Plants are a vast reservoir of phytochemicals that serve as the source of numerous drugs, including many with anticancer properties [18][19]. These phytochemicals may act on cellular signalling, apoptosis, metabolic pathways, and cell motility in tumor cells. Most anticancer research

Synthesis of depressin, cryptomeridiol and 4-epi-cryptomeridiol enabled by a terpenoid chiral pool-producing platform

• Yao Kong,
• Tao Wang,
• Chen Wang,
• Pengcheng Zhang,
• Yuanning Liu,
• Kaibiao Wang,
• Fen Liu,
• Hongli Jia and
• Zhengren Xu

Beilstein J. Org. Chem. 2026, 22, 683–690, doi:10.3762/bjoc.22.53

• Yao Kong Tao Wang Chen Wang Pengcheng Zhang Yuanning Liu Kaibiao Wang Fen Liu Hongli Jia Zhengren Xu State Key Laboratory of Natural and Biomimetic Drugs, Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China Beijing

Using generative AI to transform peptide hits into small molecule leads

• Joshua Mills and
• Yu Heng Lau

Beilstein J. Org. Chem. 2026, 22, 672–679, doi:10.3762/bjoc.22.51

• drugs derived from native peptide substrates. A classic example is the ACE inhibitor captopril, an analogue of a snake venom peptide, the development of which has been cited as an early success story for structure-based rational drug design [12][13]. Despite the long history, there is still no

Photoorganocatalytic trifluoromethylation of (het)arenes in green conditions

• Egor N. Boronin,
• Svetlana E. Kaurkina,
• Milena M. Svetlakova,
• Anton S. Bolshakov,
• Maxim V. Arsenyev,
• Vasilii F. Otvagin,
• Alexey Yu. Fedorov,
• Timothy Noël and
• Alexander V. Nyuchev

Beilstein J. Org. Chem. 2026, 22, 662–671, doi:10.3762/bjoc.22.50

• compounds play a crucial role in pharmaceuticals, agrochemicals, and advanced functional materials. A substantial fraction of newly approved drugs feature a CF3 group, reflecting its unique ability to modulate the chemical stability, lipophilicity, and biological activity of active pharmaceutical

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• HDAC6 inhibitors are not suitable to effectively treat diseases and enter the clinical trials due to a lack of selectivity, which can cause serious side effects [84]. Consequently, developing drugs targeting HDACs specifically to treat cancer is urgent. In this context, PROTACs have become a straw to

• inflammatory diseases [93][94][95][96]. So developing corresponding small-molecule drugs with the p38MAPK family as a key target is necessary. However, up to now, no small-molecule inhibitors targeting the p38MAPK family have been approved by the FDA, since every effort has failed in clinical trials [97][98

• ][99]. The reasons for the failure are rarely discussed but one of the factors is believed to be due to the inhibition of several p38MAPK proteins [98]. Therefore, how to specifically target p38MAPK family members has become a vital issue in the development of drugs. In this regard, PROTAC again shows

Regioselective approach to 5-arylsulfonylisoxazoles and their antimicrobial activity

• Artem S. Sazonov,
• Dmitry A. Vasilenko,
• Denis V. Porfiriev,
• Yuri K. Grishin,
• Rimma A. Gazzaeva,
• Alisa P. Chernyshova,
• Maxim A. Kryakvin,
• Anna A. Baranova,
• Vera A. Alferova and
• Elena B. Averina

Beilstein J. Org. Chem. 2026, 22, 592–602, doi:10.3762/bjoc.22.45

• sulfonyl or sulfinyl derivatives. Biological evaluation revealed that several compounds, especially 3-nitro-5-sulfonyl- and 5-sulfinylisoxazoles, exhibit potent antimicrobial activity against Gram-positive bacteria, fungi, and notably low MICs comparable to those of standard drugs. The mechanism of action

• -inflammatory, for the treatment of Alzheimer diseases, etc. [10][11][12][13][14][15][16]. Among the sulfonyl-containing heterocycles with confirmed efficacy against microorganisms (bacteria and fungi), sulfonylisoxazoles have attracted considerable attention as potential antibacterial drugs, with the isoxazole

• core in these compounds being essential for the activity [10]. Representative examples of biological active sulfonylisoxazoles, including marked drugs (see, for example, edonentan, sulfamethoxazole and sulfisoxazole) and compounds with the most promising activity are shown in Figure 1. Also, modern

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• , futibatinib, infigratinib, and erdafitinib, as pan-FGFR inhibitors, exhibit therapeutic efficacy against tumors driven by FGFR2. For advanced cholangiocarcinoma driven by FGFR2, infigratinib and futibatinib are targeted drugs specifically approved for this indication [19]. In contrast, erdafitinib is

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• catalysis [26]. These molecules are widely found in natural products [27] and drugs, such as michellamines A and B [28], korupensamines A and B [29], diazonamide A [30], mastigophorene A [31], and the recently developed drug candidate BMS-986142 [32] (Figure 1). When a molecule contains two or more chiral

• , the medical field is actively exploring the potential applications of multiaxial chirality in drugs and therapeutics. The development of BMS-986142 [32] has further advanced treatment strategies for tumors and lymphocytic leukemia. To date, the development of bi- and multiaxial chiral architectures

Structural reassignment of compound 968, an allosteric glutaminase inhibitor

• Lindsey A. Albertelli,
• Sainabou Jallow,
• Chun Li and
• Scott M. Ulrich

Beilstein J. Org. Chem. 2026, 22, 455–460, doi:10.3762/bjoc.22.33

• glutaminase inhibition on several cancer cell lines (Figure 1) [15][16]. The anticancer effects of compound 968 have been tested in combination with other drugs such as paclitaxel [17], erlotinib [18], apigenin [19], metformin [20], and inhibitors of tissue transglutaminase [21]. Compound 968 was recently

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• , many of which exhibit promising applications in medicinal chemistry [18][19]. Selenium has been incorporated into non-steroidal anti-inflammatory drugs (NSAIDs) and histone deacetylase (HDAC) inhibitors, both of which show considerable potential in anticancer therapy [20][21]. Over the last few decades

• anticancer drugs, such as erlotinib and gefitinib, as well as previously reported selenium- and naphthalimide-based compounds (Table 1). The comparison shows that compounds 7 and 8 have IC₅₀ values in the upper range relative to the standard drugs erlotinib and gefitinib. However, their IC₅₀ values are

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• -mimicking scaffolds are a proven strategy in the design of anticancer drugs. Many cancer-related proteins (e.g., kinases, ATPases, DNA/RNA polymerases) have binding pockets designed for purine nucleotides (ATP, GTP). Oxazolopyrimidines can compete with purines or their analogues, inhibiting enzymatic

• lines represented in the corresponding NCI60 subpanel derived from leukemia, melanoma, non-small-cell lung carcinoma, and cancers of the brain, ovary, breast, colon, kidney, and prostate [13]. These results provided evidence that the compound could be helpful in developing new anticancer drugs. The

• of drug candidate development, taking into account the expected pharmacokinetic and toxicological, as well as undesirable properties of the molecules. At the same time, drug similarity filters developed by pharmaceutical companies based on the physicochemical properties of approved drugs with known

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• of pharmaceutical use. Today, only slightly more than a dozen barbiturate-containing drugs remain in medical practice [4]. Nevertheless, interest in barbiturate derivatives resurged around the 1920s, when the first compounds containing a spirobarbiturate moiety were synthesized [5][6]. By the early

• using the free online software SwissADME (http://www.swissadme.ch/). The molecular descriptors were calculated according to Lipinski’s rule of five. This rule was formulated by Ch.A. Lipinski based on the observation that most orally administered drugs are relatively small and moderately lipophilic

• molecules [56]. By this rule, orally active drugs should not violate more than one of the following criteria: MW – molecular weight: < 500 Da; NHBD – number of hydrogen-bond donors, Log(P) – octanol/water partition coefficient: <5; NHBA – number of hydrogen-bond acceptors, NRotB – number of rotatable bonds

A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1H)-one derivatives

• Dmitrii A. Grishin,
• Kseniia I. Sharkovskaia,
• Ilya G. Kolmakov,
• Daria A. Ipatova,
• Rostislav A. Petrov,
• Nikolai D. Dagaev,
• Dmitry A. Skvortsov,
• Maria G. Khrenova,
• Valeriy V. Andreychev,
• Sergei A. Evteev,
• Yan A. Ivanenkov,
• Roman L. Antipin,
• Olga А. Dontsova and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2026, 22, 244–256, doi:10.3762/bjoc.22.18

• cycles and enables the parallel exploration of diverse chemical space. The impact of MCRs is well documented in medicinal chemistry and pharmaceutical research, including the development of several approved drugs [14][15][16][17][18]. Recently, 4-hydroxyquinoline-2(1H)-ones and their derivatives have

Synthesis of diaryl phosphates using phytic acid as a phosphorus source

• Kazuya Asao,
• Seika Matsumoto,
• Haruka Mori,
• Riku Yoshimura,
• Takeshi Sasaki,
• Naoya Hirata,
• Yasuyuki Hayakawa and
• Shin-ichi Kawaguchi

Beilstein J. Org. Chem. 2026, 22, 213–223, doi:10.3762/bjoc.22.15

• phosphates [16]. Drugs and reagents containing phosphate ester moieties were designed as analogs of these molecules [16][17][18][19][20]. Phosphate monoesters with long aliphatic chains have also been used as surfactants [21]. Phosphate triesters are utilized as flame retardants and plasticizers for polymers

Streptoquinolines A and B, new antibacterial meroterpenoids produced by Streptomyces sp. TMPU-A0679

• Akiho Yagi,
• Hitomi Tomura,
• Ami Konno and
• Ryuji Uchida

Beilstein J. Org. Chem. 2026, 22, 185–191, doi:10.3762/bjoc.22.12

• or immunocompromised patients [2]. Current treatment relies on only a few agents, including linezolid and daptomycin, and the emergence of resistant strains to these drugs poses an additional clinical challenge [3]. Therefore, the World Health Organization (WHO) revised its Bacterial Priority

Highly electrophilic, gem- and spiro-activated trichloromethylnitrocyclopropanes: synthesis and structure

• Ilia A. Pilipenko,
• Mikhail V. Grigoriev,
• Olga Yu. Ozerova,
• Igor A. Litvinov,
• Darya V. Spiridonova,
• Aleksander V. Vasilyev and
• Sergey V. Makarenko

Beilstein J. Org. Chem. 2026, 22, 123–130, doi:10.3762/bjoc.22.5

• part of the hormaomycin antibiotic [21], and also acts as a precursor for the synthesis of the aminocyclopropane [22] moiety, which is a component of some drugs, such as ciprofloxacin [23] and belactosin A [24]. Thus, the construction of cyclopropanes containing vicinal nitro- and trichloromethyl

Total synthesis of asperdinones B, C, D, E and terezine D

• Ravi Devarajappa and
• Stephen Hanessian

Beilstein J. Org. Chem. 2025, 21, 2730–2738, doi:10.3762/bjoc.21.210

• indole alkaloids is known for its biomedical importance [2]. These alkaloids have been isolated from plants [3], marine sources [4], bacterial sources [5][6][7], and they are particularly relevant primarily because of their potent pharmacological activities as among other, anticancer drugs, but also for

Competitive cyclization of ethyl trifluoroacetoacetate and methyl ketones with 1,3-diamino-2-propanol into hydrogenated oxazolo- and pyrimido-condensed pyridones

• Svetlana O. Kushch,
• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess,
• Pavel A. Slepukhin,
• Alexandrina S. Volobueva,
• Vladimir V. Zarubaev and
• Victor I. Saloutin

Beilstein J. Org. Chem. 2025, 21, 2716–2729, doi:10.3762/bjoc.21.209

• antileishmanial [47], antibacterial [48], antimalarial agents [49] as well as COX-2 [50] and FGFR [51] inhibitors found among them. Moreover, various drugs (antipsychotic risperidone [52] and pirenperone [53], antiallergic ramastine [54]) have been obtained on the basis of pyrido[1,2-a]pyrimidine; and

Tandem hydrothiocyanation/cyclization of CF₃-iminopropargyl alcohols with NaSCN in the presence of AcOH

• Ruslan S. Shulgin,
• Ol’ga G. Volostnykh,
• Anton V. Stepanov,
• Igor’ A. Ushakov,
• Alexander V. Vashchenko and
• Olesya A. Shemyakina

Beilstein J. Org. Chem. 2025, 21, 2694–2702, doi:10.3762/bjoc.21.207

• motif in various biologically active molecules and materials due to its unique physical, chemical, and biological properties [28][29][30]. SCN and trifluoromethyl groups have proved to be versatile moieties in the design and development of numerous active pharmaceutical ingredients, agrochemicals, drugs

Synthesis of new tetra- and pentacyclic, methylenedioxy- and ethylenedioxy-substituted derivatives of the dibenzo[c,f][1,2]thiazepine ring system

• Gábor Berecz,
• András Dancsó,
• Mária Tóthné Lauritz,
• Loránd Kiss,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2645–2656, doi:10.3762/bjoc.21.205

• dibenzo[c,f][1,2]thiazepine derivatives containing a 1,3-benzodioxole or, with particular emphasis, a 1,4-benzodioxane moiety. The importance of these structural motifs is well demonstrated in medicinal chemistry by marketed drugs and by compounds that have reached the human clinical development stage in

• various therapeutic fields. Launched drugs possessing a 1,3-benzodioxole element, shown in Figure 2, are among others the cough suppressant benzylisoquinoline alkaloid noscapine [4][5], the antidepressant paroxetine [6][7], antiparkinsonian agent piribedil [8][9], and tadalafil [10][11], for the treatment

• compounds are of interest, e.g., the marketed drugs eliglustat for the treatment of Gaucher’s disease [13][14] and the antihypertensive agent proroxan [15][16]. Licogliflozin is a sodium-glucose transporter 2 inhibitor developed in several indications: obesity [17], polycystic ovary syndrome [18], and non

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• available drugs [1]. These structures exhibit unique properties that influence pharmacokinetic and pharmacodynamic parameters, including lipophilicity, polarity, hydrogen-bonding capacity, and toxicological profiles [2][3][4]. Among them, five-membered multi-heterocyclic (FMMH) rings are privileged

• moieties exhibit a broad spectrum of biological activities [6][7][8]. They are found in several medicinal compounds (Figure 2), including etozoline (antihypertensive), ralitoline (anticonvulsant), thiazolidomycin (antibacterial), and in the type II diabetes mellitus drugs pioglitazone, epalrestat

• (GBB-3CR) [70][71][72]. These derivatives are of significant pharmacological and commercial interest, and are present in various commercial drugs, such as alpidem, miroprofen, necopidem, saripidem, zolimidine, and zolpidem [73]. Using the EDA-catalyzed Knoevenagel condensation reaction methodology

Efficient solid-phase synthesis and structural characterization of segetalins A–H, J and K

• Liangyu Liu,
• Wanqiu Lu,
• Quanping Guo and
• Zhaoqing Xu

Beilstein J. Org. Chem. 2025, 21, 2612–2617, doi:10.3762/bjoc.21.202

• Liangyu Liu Wanqiu Lu Quanping Guo Zhaoqing Xu Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, 199 West Donggang Road, Lanzhou 730000, China 10.3762/bjoc.21.202 Abstract This study establishes an efficient solid-phase