ABSTRACT ATR kinase is a key regulator of the DNA damage response and replication stress, with two decades of homology model‐based drug design now validated by cryo‐EM structures of full‐length human ATR‐ATRIP. This review treats ATR drug discovery as both a synthetic chemistry and structural challenge, outlining reagent‐level pathways from initial hits to drug substances for clinical candidates. It includes multi‐kilogram biocatalytic and photoredox‐flow routes for ceralasertib, analysing the strategic logic behind each scheme, a focus absent in recent SAR‐based reviews. We analyse the binding modes observed in the recent ~3 Å ATR–ATRIP inhibitor co‐structures and compare them with previous PI3K homology model predictions. Additionally, we expand the discussion on selectivity to include not only the ( R )‐3‐methylmorpholine pocket but also the aminopyrazine and macrocyclic chemotypes. The section on PROTACs is reoriented around degrading the ATR‐CHK1‐ATM pathway, highlighting a CHK1 degrader and ATM degrader that synergise with ATR inhibition. Finally, ATR's roles beyond oncology are considered, including neurodevelopment, mitochondrial homoeostasis, gametogenesis, and in parasitic DDR. Overall, in the current scenario, ATR inhibitors are positioned as promising candidates for repurposing in biomarker‐guided therapies, balancing potency, selectivity, toxicity and resistance.
ABSTRACT An effective oxidative ethynylation of 1,2,3,4‐tetrahydrobenzo[ b ][1,6]naphthyridines (THBNs) was developed. A practical improvement was achieved by optimizing a co‐catalytic system composed of O 2 , CuI, and DMAP. The co‐catalytic system allows a decrease in the loading amount of DIAD, simplifies product isolation workup and increases the yields. The co‐catalytic system proved to be effective not only with DIAD but also with the reduced forms of DIAD‐H 2 . Supported by predictions of in‐house developed ligand‐based target fishing computational tools, a series of newly synthesized 1‐phenylethynyl‐substituted THBN derivatives were evaluated against both human cholinesterases (AChE, BChE), and monoamine oxidases (MAOs A and B) as well. Most 1‐phenylethynyl‐substituted THBNs, and the respective 1‐unsubstituted derivatives, inhibited AChE and BChE at single‐digit micromolar concentrations (IC 50 = 3–10 µM). Molecular docking simulations suggested that the ethynyl substituent may engage additional hydrophobic/π–π interactions in the AChE binding sites. Notably, 12‐chloro‐1,2,3,4‐tetrahydro‐2‐methylnaphtho[2,3‐ b ][1,6]naphthyridine ( 3a ) proved to be also a potent and selective MAO A inhibitor (IC 50 = 0.237 µM, selectivity index > 40).
ABSTRACT A concise, high‐yield one‐pot protocol afforded two novel trifluoromethylated Schiff base hybrids, (E)−2,2,2‐trifluoro‐N‐(2‐((2‐hydroxybenzylidene)amino)−2‐methylpropyl)acetamide ( 1 ) and its 2‐hydroxynaphthyl analogue ( 2 ). Both combine a branched diamine core, a phenolic/naphtholic imine, and a trifluoroacetamide fragment, giving fluorinated frameworks distinct from reported donepezil and galantamine analogues, which typically use extended benzyl–piperidine architectures. Both compounds were characterised by multinuclear NMR, IR, MS and elemental analysis; their purity was established by reverse‐phase HPLC (98.8% for 1 and > 99% for 2 after recrystallisation), and their structures were determined by single‐crystal X‐ray diffraction. Crystal structure and Hirshfeld surface analyses reveal a tautomerism‐controlled switch in supramolecular assembly: compound 1 adopts an enol–imine form, generating discrete amide–phenol dimers via a robust heterosynthon, while 2 exists as a keto–enamine, forming infinite N–H···O hydrogen‐bonded chains reinforced by π–π stacking of naphthalene rings. DFT calculations (B3LYP/6‐311 + G(d,p)) support these findings, showing distinct charge distributions and a reduced HOMO–LUMO gap for 2 , consistent with enhanced electronic polarizability. Molecular docking against acetylcholinesterase (PDB: 1EVE) predicted that both compounds adopt binding modes within the catalytic gorge, with 2 showing particularly favourable interactions within the catalytic gorge. These predictions were tested experimentally. In a colorimetric AChE inhibitor screening assay both compounds inhibit the enzyme in a concentration‐dependent manner, with IC 50 values of 22.5 µM (1) and 55.0 µM (2) against 15.0 µM for the galantamine reference measured alongside. Compound 1 is the more potent of the pair, by a factor of 2.4, and comes within 1.5‐fold of the reference inhibitor, identifying the compact phenolic scaffold rather than the extended naphthalenic one as the better lead for further development. Computational ADME/Tox profiling tentatively predicts compliance with Lipinski and Veber criteria, oral bioavailability, blood–brain barrier permeation, and acceptable toxicity classes, pending experimental confirmation. Overall, this work establishes a synthetically accessible, structurally tunable family of trifluoromethylated scaffolds whose solid‐state behaviour and preliminary computational pharmacology indicate potential as crystallography‐guided AChE inhibitor candidates warranting further investigation.
ABSTRACT Breast cancer (BC) is the second most common cause of death in women. Current therapies like hormonal therapy, surgery, radiotherapy, and chemotherapy become ineffective due to severe side effects and multidrug resistance. Therefore, there is an urgent need for the development of more effective and safer anti‐BC agents. Among different classes of heterocyclic molecules, indazole‐based derivatives have emerged as potent anti‐BC agents due to their versatile structural features and wide range of biological targets. Indazole is a benzene‐pyrazole fused system with potential biological therapeutic significance. This review provides a detailed overview of recent progress in strategies that have expanded the accessible structural diversity of this scaffold. Moreover, mechanistic insights reveal that indazole derivatives mediate their antitumor effects through multi‐target modulation, including the inhibition of key kinases such as EGFR, VEGFR, and CDKs, perturbation of microtubule function, activation of apoptotic pathways, and modulation of hormone receptor‐dependent signalling, along with SAR. Collectively, this article is a BC‐focused integration of different synthetic approaches, the key molecular targets for therapy, and studies showing which groups are responsible for their anti‐BC potential, focusing on the latest research published.
ABSTRACT Alzheimer's disease is a severe condition that poses significant global health concerns to international health agencies and remains a major threat to public health. As there is no cure for Alzheimer's disease, various anti‐Alzheimer's medications are used to manage its symptoms. Donepezil is one of the most highly marketed drugs, known for its positive effects on cognition, function, behaviour and overall patient condition, making it a standout treatment option. Various synthetic methods have been developed to produce more efficient pathways that minimise by‐products and maximise yield. This review summarises the reported literature on various synthetic routes for producing Donepezil . We have also made an effort to highlight the advantages and limitations of prior literature, which may lead to potential improvements for future research. This work will serve as a foundation for upcoming researchers, ultimately benefiting the well‐being of Alzheimer's patients and human society as a whole.
