Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• have low to negligible inhibition potential but dialkylated ones have no inhibition potential at all for directed CAs (I, II, IX, and XII). From the low inhibiting compounds, 7b showed the highest inhibition potential with a minimum Ki value of 72.9 μM. In light of the above findings, these newly

• types of CAs (CA II, CA IX and CA XII). Among these low active compounds, the highest inhibition (Ki = 72.9 μM) was shown by compound 7b for the CA IX type. This compound also exhibited low to negligible inhibition with Ki values of 77.4 and 90.9 μM for CA XII and CA II, respectively. The compounds with

• very low CA II inhibition (Ki = 90–95 μM) include 7c, 7f, and 7h. Again very low inhibition activity with Ki values 90 to 95 μM was exhibited by compound 7a for CA XII and compound 7h for CA II, CA IX, and CA XII, respectively. Slight inhibition potential with Ki values 79 to 88 μM was shown by 7a for

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• % yield over 2 steps) [34]. Upon exposure to NaNO2/HCl, diamine 3 was transformed into a diazonium salt, which was captured by KI to deliver the diiodide 4. Treatment of 4 with n-BuLi, PhPCl2, and H2O2 sequentially gave 2,8-difluoro-5-phenylbenzo[b]phosphindole 5-oxide (5) in 68% yield. With compound 5 in

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• by HVI compounds are less prevalent compared to other halocyclisations. The use of PhI(OAc)2 with KI or TMSI as the iodide source has been reported to promote iodocyclisation in unsaturated compounds with internal nucleophiles. Nitrogen nucleophiles In addition to both chloro- and bromoaminations

• , Liu and Li reported intramolecular iodoamidiation of unsaturated amines in 2014 (Scheme 42) [30]. Using PIDA as an oxidant and KI as a source of iodide, iodinated pyrrolidines 80 were synthesized in excellent yields under mild conditions of CH2Cl2 at room temperature. A range of unsaturated amines

• also demonstrated the formation of 3-bromoindoles 66 (Scheme 43) [54]. In this instance, KI was used as the iodide source with PIDA in HFIP. The mechanism proposed was the same as that for the bromoindoles (Scheme 35). Oxygen nucleophiles In addition to chloroamidation and chlorolactonization

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

Finding the most potent compounds using active learning on molecular pairs

• Zachary Fralish and
• Daniel Reker

Beilstein J. Org. Chem. 2024, 20, 2152–2162, doi:10.3762/bjoc.20.185

• from the current best training compound to prioritize further data acquisition. We apply the ActiveDelta concept to both graph-based deep (Chemprop) and tree-based (XGBoost) models during exploitative active learning for 99 Ki benchmarking datasets. We show that both ActiveDelta implementations excel

• the Chemprop-based [20] and XGBoost-based [21] implementations of this learning strategy against standard exploitative active learning [19] implementations of Chemprop [20], XGBoost [21], and Random Forest [22] across 99 Ki datasets with simulated time splits [23]. Across these benchmarks, the

• . Methods Datasets Datasets were obtained from Landrum et al. [23] which utilized their simulated medicinal chemistry project data (SIMPD) algorithm to curate and split 99 ChEMBL [24] Ki datasets with consistent values for target id, assay organism, assay category, and BioAssay Ontology (BAO) format into

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

• α4β2 nicotinic cholinergic receptor ligands with nanomolar activities in rat brain homogenates (Scheme 2). The idea behind these AEP structures was to check activity correlation against a nicotine series. The comparison of Ki values of both series showed a moderate correlation, which opens the

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• in the presence of Bu4NHSO4 (Table 1, entry 9) and the use of Bu4NCl (Table 1, entry 8) was not satisfying either. On the other hand, the beneficial effect of the quaternary ammonium functionality was clearly underscored by employing KI instead of Bu4NI (compare Table 1, entries 10 and 5). While

• Bu4NI allowed for the clean and selective formation of 1a, we observed significant amounts of the α-I-ketoester 3 when using KI instead. Having established the combination of DBPO and Bu4NI as the best-suited catalyst/oxidant combination for the α-azidation of 1a using NaN3, we finally optimized

• additional KI in the presence of DBPO) and then resubmitted this compound to our ammonium salt-catalyzed azidation reaction conditions, observing full conversion to 2a as well. Considering all these details we thus propose a mechanistic scenario as outlined in Scheme 2. The catalyst gets oxidized to Bu4NIO

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• -neutral phosphinamide and a negatively charged phosphinic acid derivative had excellent stability in water at pH 7.4, but only the charge-neutral compound inhibited human CDA, similar to previously described 2'-deoxyzebularine (Ki = 8.0 ± 1.9 and 10.7 ± 0.5 µM, respectively). However, under basic

• , IV), with an inhibition constant (Ki) of 0.9 nM (Figure 1B) [45]. However, it is unstable in solution and thus cannot be used as CDA inhibitor or incorporated into ssDNA and evaluated as an A3 inhibitor. Here, we report the synthesis of novel inhibitors of CDA and A3 based on the 1,4-azaphosphinine

• equation, such as Lineweaver–Burk, Hanes–Woolf and Eadie–Hofstee transformations [71]. Then, KM for the substrate and Ki for each inhibitor were calculated, assuming competitive nature of the inhibitors (Table 1). Initially, we performed this assay in 50 mM sodium phosphate buffer at pH 7.4 (25 °C) and

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• ., in two different periods, reported two paradigmatic examples for indole syntheses. In 2010, they developed the synthesis of 1-(alkoxyarylmethyl)indole-3-carboxylic esters from 2-alkynylaniline imines by using PdI2/KI as catalyst system and oxygen as oxidant [15]. In particular, the reaction was

• carried out using 2 mol % of PdI2, 20 mol % of KI and 40 bar of a 4:1 mixture of CO–air, in methanol or ethanol in the presence of an ortho-ester (1:3 mixture) as solvent to prevent hydrolysis of the substrate. After 15 hours at 80 °C the indoles derivatives were isolated in good yields (Scheme 4). Two

• the formation of N-substituted indole derivatives from N-substituted anilines. The direct PdI2/KI oxidative carbonylation of 2-alkynylanilines does not lead to the formation of indole-3-carboxylic esters but to the formation of acyclic carbamates. For this reason, they performed the reaction in the

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• ; FeSO4 1 µM; KI 2 g/L, KCl 2 g/L, KBr 2 g/L, NaNO2 2 g/L; H2O2 20 µM; (methyl jasmonate) MeJA 10 µM). XISR III medium (yeast extract 4 g/L; soy flour 10 g/L; glucose 30 g/L; MgCl2 1 µM; FeSO4 1 µM; KI 2 g/L, KCl 2 g/L, KBr 2 g/L, NaNO2 2 g/L; H2O2 20 µM; MeJA 10 µM; 5-azacytidine 6 µM; suberoylanilide

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• efficient quenching using KI instead of NaI to the better size affinity of the podand with potassium. Even though this system seemed promising, podand-based molecular tweezers have not attracted much interest for switchable molecular tweezers design until the work of Fan and co-workers in 2014 [67]. They

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• benzothiazole, in which benzothiazole compounds have higher reactivity and regioselectivity than thiazole. In 2014, Lei et al. successfully realized the copper-catalyzed oxidative alkenylation of simple ethers to construct allyl ethers in the presence of di-tert-butyl peroxide and KI (Scheme 10) [60]. The

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• : LManII from Drosophila melanogaster and JBMan from Canavalia ensiformis) were investigated. 6-Deoxy-DIM was found to be the most potent inhibitor of AMAN-2 (Ki = 0.19 μM), whose amino acid sequence and 3D structure of the active site are almost identical to the human α-mannosidase II (GMII). Although 6

• inhibition constants (Ki) up to 4 µM and selectivity indices (SI) up to 350. However, these enhancements were found to be significant only for those N-substituted analogs that bore N-alkyl chains without an additional aryl moiety [30][31][32] (Figure 1). Next, we turned our attention to modifications of 1,4

• than analogues 17–19 toward the GH38 enzymes tested. Thus, it appears that N-substitution of the free iminosugar 20 considerably reduces the inhibitory activity. Among imino-ᴅ-lyxitols 26–29, 6-deoxy-DIM 29 was found to be the most potent derivative (Ki = 0.065 μM and 0.19 μM for GMIIb and AMAN-2

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• derivative 3aa with 72% isolated yield (Table 1, entry 1). Other iodide sources, such as LiI, KI, RbI, CsI, CaI2, and a quaternary ammonium iodide, while also effective, provided slightly lower yields (Table 1, entries 2–7). It should be noted that all tested iodide sources were found soluble under those

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

• Neda Rafieiolhosseini,
• Matthias Killa,
• Thorben Neumann,
• Niklas Tötsch,
• Jean-Noël Grad,
• Alexander Höing,
• Thies Dirksmeyer,
• Jochen Niemeyer,
• Christian Ottmann,
• Shirley K. Knauer,
• Michael Giese,
• Jens Voskuhl and
• Daniel Hoffmann

Beilstein J. Org. Chem. 2022, 18, 1322–1331, doi:10.3762/bjoc.18.137

• the total energy. where ki is the spring constant, li is the distance between bonded beads i and i+1, and lieq is the corresponding distance at equilibrium, Eg represents the affinity of protein toward GCP or lysine at a specific grid point. In this study, l1 and l4, i.e. the equilibrium lengths for

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• a reversible acidochromic behavior [30]. Zhao et al. demonstrated a three-component transition-metal-free aerobic method using a KI/DMSO/O2 system for the facile generation of iminobenzo-1,4-thiazines in moderate to good yield [31]. 3,4-Dihydro-2H-benzo-1,4-thiazine derivatives 6 were also

Shift of the reaction equilibrium at high pressure in the continuous synthesis of neuraminic acid

• Jannis A. Reich,
• Miriam Aßmann,
• Kristin Hölting,
• Paul Bubenheim,
• Jürgen Kuballa and
• Andreas Liese

Beilstein J. Org. Chem. 2022, 18, 567–579, doi:10.3762/bjoc.18.59

• particular, the circular reactor showed great potential to study reactions at high pressure while allowing for easy sampling. Additionally, an increase in affinity of pyruvate towards both tested enzymes was observed when high pressure was applied, as evidenced by a decrease of KI for the epimerase and KM

• pressure on the inhibition by pyruvate was measured and is shown in Figure 9. The value for the inhibition constant is in the same order of magnitude as results of other groups, measured at ambient pressure (0.146 ± 0.019 mol/L [5]). Since the KI value changes with pressure (Table 4), the concentrations

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• 3a–h were tested at 1.0 mM in the presence of the donor substrate MUNANA (0.1 mM) along with pyridoxal phosphate (PLP, Ki = 7.3 mM) [35] and 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA) [36] as positive controls for TcTS and neuraminidase, respectively. Surprisingly, the results showed

Chemoselective N-acylation of indoles using thioesters as acyl source

• Tianri Du,
• Xiangmu Wei,
• Honghong Xu,
• Xin Zhang,
• Ruiru Fang,
• Zheng Yuan,
• Zhi Liang and
• Yahui Li

Beilstein J. Org. Chem. 2022, 18, 89–94, doi:10.3762/bjoc.18.9

• structural, chemical, and biological properties [1]. For example, indomethacin is a nonselective inhibitor of COX1 and COX2, which is used for treating fever, pain and swelling [2]. Indole analog L-768242 exhibits nanomolar potencies (Ki) with superior selectivity for the hCB2 receptor over the human central

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• oxidative conditions, catalyzed by CuTC to give the desired product 101 (Scheme 15a). On the other hand, Yang synthesized bis(indol-3-yl)sulfides 105 through the reaction of indole with elemental sulfur, catalyzed by iron(II) sulfate in the presence of stoichiometric amounts of KI in air [83]. The I− from

• KI formed ferrous iodide, which reacts with indole to form the iron bis-indolide 107, followed by reaction with N,N-dimethylmethanethioamide to get the S atom inserted (108). A reductive elimination then generated the bis(indol-3-yl)sulfides 105 along with Fe0, which was re-oxidized by aerial oxygen

• presence of stoichiometric KI and catalytic amounts of FeII for the synthesis of similar bis(indol-3-yl)selanes (Scheme 18c) [83]. In 2018 Thurow reported a method using stoichiometric SeO2 along with sub-stoichiometric PhSSPh (138) to obtain a mixture of the desired diindol-3-ylselane (137a) along with

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

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• nitrogen protection (Scheme 3). A first attempt here involved the reaction of 5 with PMBCl in DMF, using K2CO3 alongside KI. Two separable regioisomers 11 and 12 were isolated in an acceptable 53% overall yield and in a ratio of N1-PMB/N2-PMB = 1.1:1 (Scheme 3). HMBC NMR of 11 and 12 clarified the position

• , DMAP, DMF, rt, 24 h, 87%; h) TMSN3, Bu2SnO, toluene, 120 °C, 51%. a) PMBCl, KI, K2CO3, DMF, rt, 53% for 11 and 12; b) BnBr, DMF, Et3N, DCM, rt, 31% for 13 and 14. a) DMSO, SO3·pyridine, Et3N, rt, 1 h, 96%; b) H2NOH·HCl, THF, H2O, Na2CO3, 89%; c) POCl3, MeCN, 65 °C, 59%; d) TMSN3, Bu2SnO, toluene, 120

• °C, 55%; e) PMBCl, KI, K2CO3, DMF, 76% for 18 and 19; f) 3-(benzyloxycarbonylamino)-propan-1-ol, NIS, AgOTf, CH2Cl2, −40 to −10 °C, 3 h, 34%; g) H2(g), Pd/C, Pd(OH)2/C, HCl, EtOH, THF, rt, 56 h, 96%; h) dibenzyl phosphate, NIS, AgOTf, CH2Cl2, −30 to 0 °C, 3.5 h, 72%; i) H2(g), Pd/C, Pd(OH)2/C, 5

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• previously reported to bind to the cannabinoid receptors, CB1 (Ki 4.3 µM) and CB2 (Ki 1.1 µM) [41]. Both receptors are considered important therapeutic targets, e.g. for neurodegenerative and inflammatory diseases. Selected final products (3a, 3b, 3e, 3g, 3h, 3n, 3ad) were tested for their binding affinities

• bearing 5-OMe,6'-F (3e), 5-OMe,7'-Br (3g), and 5-OMe,5',6'-diF substitution (3h) exhibited similar binding affinities to lead compound I. 5,6-DiF-DIM derivative 3n (CB1: Ki 2.04 µM) showed a slightly improved binding affinity compared to lead compound I. These results suggest that compounds with small

• substituents like fluoro on only one indole ring are favorable for CB receptor binding. The pentafluoroethylated DIM derivative 3ad was the best CB1 ligand of the present series with a Ki value of 1.82 µM. The binding curves of 3e and 3ad are depicted in Supporting Information File 1, Figure S1. Compound 3e

Total synthesis of decarboxyaltenusin

• Lucas Warmuth,
• Aaron Weiß,
• Marco Reinhardt,
• Anna Meschkov,
• Ute Schepers and
• Joachim Podlech

Beilstein J. Org. Chem. 2021, 17, 224–228, doi:10.3762/bjoc.17.22

• . Biphenyl-derived mycotoxins. Synthesis of arylboronates 6. Conditions: a) TBSCl, DMAP, imidazole, DMF, 50 °C, 4 h (96%); b) NBS, MeCN, rt, 71 h (quant.); c) NBS, MeCN, rt, 72 h (R = TBS, 96%); d) BnBr, KI, K2CO3, DMF/acetone, 70 °C, 29 h, (R = Bn, 86%); e) R = TBS: BuLi, 2-isopropoxy-4,4,5,5-tetramethyl

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• pyrrole-3-carboxamides. In the presence of 1.2 equiv of KI, a polysubstituted pyrazolo[3,4-b]pyridine derivative was also successfully synthesized. Keywords: acid catalyst; [1 + 2 + 2] annulation; KI; pyrazolo[3,4-b]pyridine; pyrroles; Introduction Among nitrogen-containing heterocycles, pyrroles have

• synthesis, we also observed an unexpected reaction in which the pyrazolo[3,4-b]pyridine scaffold was constructed under analogous conditions. As shown in Scheme 6, In the presence of a catalytic amount of AlCl3 and 1.2 equiv of KI, 3-methyl-1-phenyl-1H-pyrazol-5-amine (1b) reacted smoothly with 2a and 3a

• aromatization to produce 5a. KI may play a key role in the last step, and we suspected that it can promote the removal of bromide. Although 5a can theoretically be synthesized through a three-component reaction of 1b, 2a, and an appropriate aldehyde, for example, acetaldehyde [50][51] owing to the insufficient