Abstract Drug resistance is a looming threat to global health security, undermining the effectiveness of current treatments and increasing treatment failures. To address this challenge, it is necessary to explore innovative strategies by identifying new binding mechanisms and targeting previously undeveloped therapeutic avenues. This paper reviewed the potential of leveraging undeveloped domains to combat drug resistance and proposes a range of methodologies to accurately identify those specific targets. There is also an extensive review of the challenges associated with targeting undeveloped areas and strategies to effectively address them. In this process, the application of artificial intelligence (AI) can effectively improve the efficiency of drug design, while appropriate attention should be paid to the physicochemical and drug-like properties of pharmaceutical compounds in the realm of drug discovery. Given the above, focusing on these undeveloped areas could provide a promising pathway to address drug resistance; however, achieving this objective necessitates sustained investigative efforts and inventive approaches.

Ischemic stroke remains the leading cause of death worldwide, and in experimental studies of ischemic stroke, neuroprotective agents may display good efficacy. In our previous work, Fenazinel showed promising neuroprotective effects and entered phase I clinical trials in China. However, some side effects have limited its further study. To explore novel neuroprotective agents with higher potency and lower cardiotoxicity, in this work, a series of Fenazinel derivatives with piperidine urea groups (A1–A13) were designed and synthesized. The neuroprotective effect of A1–A13 was evaluated in human neuroblastoma cells (SH-SY5Y) by assessing cell survivals, and then in a rat model of middle cerebral artery occlusion (MCAO) by assessing the cerebral infarction area. The hERG (human ether-a-go-go-related gene) inhibitory activity was conducted to predict the cardiotoxicity of compounds. The hypoxia tolerance assay of mice was assessed by determining the survival time of mice in a sealed bottle. Our experimental data suggested that among the compounds, compound A10 demonstrated superior protective activity against SH-SY5Y cells at different concentrations, lower cytotoxicity compared with Fenazinel, and additionally, a weak cardiotoxicity (hERG IC50 > 40 μmol/L). Compound A10 not only effectively prolonged the survival time of mice, but also significantly reduced the percentage of cerebral infarction in MCAO rats with a dose-dependent tendency. In summary, this paper provides a reference for the rational structural medication of Fenazinel to reduce cardiotoxicity and finds compound A10 with better neuroprotective activity.

Abstract Hypoxia-inducible factors (HIFs) play a key role in regulating cellular responses to low-oxygen conditions, particularly in promoting angiogenesis in tumor microenvironments. Aberrant HIF signaling enhances tumor growth and contributes to resistance against chemotherapy and radiotherapy. Targeting the HIF pathway has emerged as a promising strategy for cancer therapy. This study aimed to identify novel inhibitors of HIF signaling and evaluate their potential against the HIF–vascular endothelial growth factor (VEGF) axis for antiangiogenic therapy. In screening our in-house drug library using hypoxia response element dual-luciferase assay, HST3782, a novel 3-hydroxy-8-azabicyclo[3.2.1]octane-bridged compound, was identified as a promising HIF inhibitor, with IC50 of 1.028 μmol/L. In this work, the inhibitory effect of HST3782 on HIF signaling was confirmed in triple-negative breast cancer cells (SUM159) under hypoxic conditions (1% O2). Quantitative real-time polymerase chain reaction suggested the inhibitory effect of HST3782 on the expression of angiogenic genes, including VEGFa, VEGFR-1, BNIP3, and SERPINE1 in 786-O cells. Zebrafish model testing revealed that HST3782 inhibited intersegmental and subintestinal vessel development by up to 56% without marked toxicity. HST3782 was synthesized through a two-step 1,2,4 triazole cyclization reaction, followed by amide formation and ketone reduction steps. The last step of hydrogenation with sodium borohydride yielded a pair of endo-exo isomers. 2D-NOESY (Nuclear Overhauser effect spectroscopy) analysis confirmed that the compound's endo isomer (HST3782) had superior inhibitory effects relative to its exo form (8b). Given the above, HST3782 is a novel HIF inhibitor, with strong antiangiogenic effects and presents a valuable scaffold for future development of antiangiogenic drugs targeting the HIF–VEGF axis. Further studies are warranted to optimize HST3782's pharmacokinetics and therapeutic efficacy for antiangiogenic therapy in hypoxia-related malignancies.

Abstract The design and synthesis of drug molecules is a pivotal stage in drug development that traditionally requires significant investment in time and finances. However, the integration of artificial intelligence (AI) in drug design accelerates the identification of potential drug candidates, optimizes the drug development process, and contributes to more informed decision-making. The application of AI in molecular generation is changing the way researchers explore the chemical space and design novel compounds. It accelerates the process of drug discovery and materials science, enabling rapid exploration of the vast chemical landscapes for the identification of promising candidates for further experimental validation. The application of AI in predicting reaction products accelerates the synthesis planning process, contributes to the automation of synthetic chemistry tasks, and supports chemists in making informed decisions during drug discovery. This paper reviewed the recent advances in two interrelated areas: the application of AI in molecular generation and synthesis routes. It will provide insights into the innovative ways in which AI is transforming traditional approaches in drug development and predict its future progress in these key fields.

Abstract Sulfonamides are one of the most important synthons in drug synthesis, which can increase the water solubility of drugs and regulate their metabolism in vivo. According to statistics, nearly 30% of sulfur-containing drugs on the market contain sulfonamide groups, including omeprazole, hydrochlorothiazide, and other best-selling drugs. Synthesis of sulfonamide is therefore a very important part of new drug development and active pharmaceutical ingredient manufacturing. In this review, we will focus on the recent 5-year advances in the field of synthetic research and structural modification of sulfonamide-containing drugs and their intermediates. The synthesis strategies, including S−N construction, C−N cross-coupling, N−H functionalization, and C−H sulfonamidation, are discussed, hoping to provide new ideas for the researchers to prepare sulfonamides in a green and efficient way.

Ricolinostat (1) is the first orally available histone deacetylase 6 inhibitor in phase II clinical trials. The results from phase II clinical studies showed that the combination of Ricolinostat with bortezomib and dexamethasone is safe and active for the treatment of multiple myeloma. However, the reported synthesis routes of Ricolinostat were plagued by several limitations, including severe reaction conditions, elevated cost factors, and the employment of environmentally unfriendly reagents. This study aimed to improve the synthesis process of Ricolinostat, in which ethyl 2-chloropyrimidine-5-carboxylate (2) was used as the starting material, the target product was obtained through the reaction of nucleophilic aromatic substitution, the Ullmann coupling, hydrolyzation amide condensation, and aminolysis. The nucleophilic substitution (2 to 3) was performed in the presence of 1.2 equiv. aniline, 2.0 equiv. K2CO3 under 100°C, with a yield of 96%; the Ullmann reaction was performed in the presence of 0.5 equiv. CuI and 2.0 equiv. cesium carbonate; the post-processes of 3 and the desired product (1) that previously required column chromatography were replaced with recrystallization using the solvent of EtOH/H2O and DMF/H2O, respectively. Through the improved process, Ricolinostat was obtained with an isolated yield of 65.8% and a purity of 99.73%, which was much higher than the reported study. This route was both cost-effective and eco-friendly, making it suitable for industrial applications.

Abstract In the fields of drug synthesis and fine chemicals, the traditional kettle-type reactor with a small heat exchange area and the microreactor which is easy to clog, are not suitable for the reaction with fast reaction speed, large heat release, and high solid content. However, the continuously stirred reactor has the advantages of high mass and heat transfer efficiency, high reaction safety, and not easy to be clogged, and therefore, has a great potential for application. This paper reviews the research progress of continuous agitation reactors in organic synthesis, drug crystallization, and biocatalysis, hoping to provide a reference for applications of continuous agitation reactors in the pharmaceutical and chemical fields.

Bacterial infections, especially those caused by drug-resistant bacterial pathogens, are crucial diseases that damage human health. In recent decades, several important boron-containing drugs have been marketed as anticancer agents or anti-infective adjuvants. Among them, vaborbactam revitalizes the antibacterial effects of meropenem against bacteria by inhibiting β-lactamases, opening a new field for addressing bacterial resistance. In this article, the chemical features of boron atoms and the typical antibacterial agents and adjuvants of boron-containing compounds are reviewed. In this work, boron-containing agents are classified into four categories according to their action mechanisms: β-lactamase inhibitors, leucyl-tRNA synthetase inhibitors, LexA self-cleavage inhibitors, and NorA efflux pump inhibitors. This review provides actionable insights for addressing the increasingly severe drug-resistant infections of bacterial pathogens.

Abstract Resveratrol (Res), an active ingredient derived from a multitude of plants, exhibits multiple pharmacological activities. However, its poor water solubility and low bioavailability present significant challenges to its clinical application. Our study aimed to improve the transdermal absorption of Res using dissolving microneedle (MN) technology, which could effectively overcome the stratum corneum barrier. Res-loaded dissolving microneedles (Res-MNs) were fabricated using polyvinyl pyrrolidone K90 (PVP K90) as the matrix material, and a two-step casting procedure was employed. The process was optimized using the Box–Behnken experimental design approach. The characteristics of Res-MNs in vitro, including morphology, solubility, safety evaluation, and skin permeation, were studied. The results showed that the optimum preparation conditions of Res-MNs were a centrifugation time of 10 minutes, a solvent concentration of 25%, and a prescription ratio (Res: matrix) of 0.375. The skin permeability of the Res-MNs was enhanced compared with Res suspension and Res gel. The cumulative release of Res-MNs in vitro was 75%, which was approximately 5 and 3 times that of the Res suspension group and Res gel group. These results suggest that dissolving MNs may represent a potential approach for enhancing the transdermal delivery of poorly absorbed drugs such as Res.