Anti-microbial resistance has become a serious global health issue affecting millions of people worldwide. Despite extensive drug discovery efforts aimed at identifying potent molecules for effective anti-microbial treatments, the emergence of superbugs remains a significant challenge. Thus, developing novel therapeutic agents is required to combat these evolving threats. The quinoxaline scaffold emerges as a promising heterocyclic framework for developing novel anti-microbial agents. It's simple, flexible structure, coupled with its bioisosteric relationship to extensively explored quinoline and naphthalene scaffolds, offers a potential avenue for circumventing bacterial resistance developed against these established classes. Hence it has sparked interest in researchers to develop novel antibiotics based on the quinoxaline core. This review focuses on the recent advances of quinoxaline derivatives as anti-microbial agents and their structure-activity relationship studies based on the literature published from 2015 to 2024. The systematic presentation of this information will assist researchers in identifying key substitution patterns around the quinoxaline nucleus, facilitating the development of structure-activity relationship (SAR), and guiding the design of novel anti-microbial drugs to combat the growing threat of anti-microbial resistance.

Cyclin-dependent kinases (CDKs) are pivotal regulators of the cell cycle and transcriptional machinery, making them attractive targets for cancer therapy. While CDK inhibitors have demonstrated promising clinical outcomes, they also face challenges in enhancing efficacy, particularly in overcoming drug resistance. Combination therapies have emerged as a key strategy to augment the effectiveness of CDK inhibitors when used alongside other kinase inhibitors or non-kinase-targeted agents. Dual-target inhibitors that simultaneously inhibit CDKs and other oncogenic drivers are gaining attention, offering novel avenues to optimize cancer therapy. Based on the structural characterization and biological functions of CDKs, this review comprehensively examines the structure-activity relationship (SAR) of existing dual-target CDK inhibitors from a drug design perspective. We also thoroughly investigate the preclinical studies and clinical translational potential of combination therapies and dual-target inhibitors. Tailoring CDK inhibitors to specific cancer subtypes and therapeutic settings will inspire innovative approaches for the next generation of CDK-related therapies, ultimately improving patient survival.

Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease characterized by fibroblast proliferation, excessive extracellular matrix buildup, inflammation, and tissue damage, resulting in respiratory failure and death. Recent studies suggest that impaired interactions among epithelial, mesenchymal, immune, and endothelial cells play a key role in IPF development. Advances in bioinformatics have also linked epigenetics, which bridges gene expression and environmental factors, to IPF. Despite the incomplete understanding of the pathogenic mechanisms underlying IPF, recent preclinical studies have identified several novel epigenetic therapeutic targets, including DNMT, EZH2, G9a/GLP, PRMT1/7, KDM6B, HDAC, CBP/p300, BRD4, METTL3, FTO, and ALKBH5, along with potential small-molecule inhibitors relevant for its treatment. This review explores the pathogenesis of IPF, emphasizing epigenetic therapeutic targets and potential small molecule drugs. It also analyzes the structure-activity relationships of these epigenetic drugs and summarizes their biological activities. The objective is to advance the development of innovative epigenetic therapies for IPF.

As an epigenetic enzyme, Lysine-specific demethylase (LSD1) has emerged as a promising target for cancer therapy. Based on the structure of tranylcypromine indazole, a series of LSD1 inhibitors have been designed and synthesized in this work. Most compounds have excellent inhibitory activity against LSD1. The representative compound, 9e, proved to be a highly effective LSD1 inhibitor, with an IC value of 9.85 nM, and demonstrated exceptional selectivity for LSD1 over both MAOs and hERG. Meanwhile, compound 9e exhibited significant inhibitory activity against leukemia cells, especially MV-4-11, HL-60, and THP-1 cells, with IC values of 1.40, 1.54, and 1.96 μM respectively. Additional biological mechanisms suggested that compound 9e could directly target LSD1 and inhibit LSD1 in MV-4-11 cells, resulting in a significant increase in the expression levels of H3K4me1/2. In addition, compound 9e was found to induce apoptosis and upregulate of CD86-expression in MV-4-11 cells. All these findings indicated that compound 9e, a tranylcypromine-indazole derivative, provided a structural basis for LSD1 inhibitors in the treatment of acute myeloid leukemia.

The Dimroth Rearrangement (DR) is an isomerization process involving the translocation of exo- and endocyclic nitrogen atoms in heterocyclic systems via a ring opening, rotation, and ring closure mechanism. Originally discovered over 120 years ago, the mechanistic occurrence of the DR on multiple heterocycles has been widely studied, and its application to the synthesis of biologically active compounds is well documented, albeit on some occasions not directly referenced. A surprisingly high number of drug discovery programs take advantage of the DR for the synthesis of heterocycle-containing compounds, including 4-aminopyrimidines and 4-anilinoquinazolines. Evidence of the flexibility and valuable potential of the DR can be found in the use of this reaction in the manufacture processes of several active pharmaceutical ingredients (APIs) on a commercial scale, allowing a reduction in the manufacturing costs and the environmental burden of the synthetic routes. The aim of this review is to outline the generality and broad applicability of the DR to the synthesis of biologically active compounds and highlight the opportunities to utilize this tool more widely within the medicinal chemistry toolbox.

The occurrence and development of diseases are complex, and single-target drugs that affect only a single target or pathway often fail to achieve the expected therapeutic effect. The simultaneous effect on two key targets could not only increase patient tolerance but also accelerate disease remission. Dual-target inhibitors have already been studied the most intensively in the development of dual-target drugs. This article briefly introduces the function of drug therapy targets, and mainly summarizes the design strategies and research progress of dual-target inhibitors in neurodegenerative diseases, infectious diseases, metabolic diseases and cardiovascular diseases.

The KRAS mutation, which occurs in approximately 14 % of lung adenocarcinomas, has recently become a crucial target for therapy via small molecules that covalently bind to the mutated cysteine. In this study, a novel series of pyrrolopyrimidine derivatives was rationally designed and synthesized, employing a structure-based drug design strategy. Through structure-activity relationship (SAR) analysis, compound SK-17 emerged as a direct and highly potent inhibitor of KRAS. Cellular assays illustrated that SK-17 exhibits potent antiproliferative effects, induces apoptosis, possesses anti-tumor metastasis properties, and effectively inhibits the downstream KRAS pathway in a dose-dependent manner. Moreover, the synergistic enhancement observed when SK-17 is combined with SHP2 inhibitors in vitro underscores its innovative potential in combinatorial therapies. In the xenograft mouse model, SK-17 demonstrated outstanding tumor growth suppression with good safety. Importantly, the in vivo test results show that compound SK-17 has a superior PK profile and lower toxicity in zebrafish test. These results demonstrated the potential of SK-17 with novel scaffold as a promising lead compound targeting KRAS to guide in-depth structural optimization.

Bruton's tyrosine kinase (BTK) has been an attractive target in the B-cell malignancies. Significant progress has been achieved in developing effective BTK-targeting small-molecule inhibitors and proteolysis targeting chimeras (PROTACs). Based on noncovalent inhibitor ARQ-531, we previously developed two potent BTK PROTACs 6e and SC-3e, which exhibited poor pharmacokinetic property. Herein, we present our extensive structure-activity relationship (SAR) studies focused on BTK binder, linker and cereblon (CRBN) ligand of SC-3e, resulting in two novel BTK PROTACs FDU28 (compound 25) and FDU73 (compound 27). Compounds 25 and 27 selectively induced rapid and robust degradation of wild type (WT) and C481S mutant BTK in a concentration-, time- and ubiquitin-proteasome system (UPS)-dependent manner without affecting CRBN neo-substrates. Furthermore, compound 27 displayed excellent cell antiproliferative activities, metabolic stability in mouse liver microsomes and improved bioavailability in mice. Overall, 27 is a highly effective and selective BTK degrader that is suitable for in vivo efficacy investigations.

Malaria, caused by Plasmodium parasites and transmitted by Anopheles mosquitoes, remains a significant global health challenge, especially in tropical and subtropical regions where the disease is endemic. The complex Plasmodium lifecycle, involving stages in both the liver and bloodstream, leads to symptoms such as high fever, anemia, and, in severe cases, life-threatening complications, particularly P. falciparum infections. While historical treatments such as quinine and modern therapies such as artemisinin-based combination therapies (ACTs) have been effective, the growing issue of drug and insecticide resistance undermines these efforts. This resistance has spurred the need for new antimalarial drugs and strategies. Among the promising areas of research are heterocyclic compounds, which, due to their diverse and versatile chemical structures, are being investigated for their ability to disrupt the Plasmodium lifecycle. These compounds have potential as novel therapeutic agents that could enhance current treatment options. Understanding the mechanisms underlying drug resistance and advancing these therapeutic innovations are crucial for maintaining effective malaria control and treatment, highlighting the importance of on-going research in this field.

Designing new radiolabeled hypoxia-targeted drugs is of great help in the diagnosis of tumors. Hypoxia-targeted drugs with dual bioactive groups can enhance hypoxia selectivity, strengthen the binding of drugs to targets, and improve diagnostic accuracy compared with traditional hypoxia-targeted drugs containing only one nitroimidazole group. In this study, a series of novel radioiodine labeled tyrosine derivatives containing 2-nitroimidazole and benzenesulfonamide groups were synthesized and in vitro evaluated. In the uptake experiments of S180 cells that didn't express carbonic anhydrase IX (CAIX), the compound [I]-3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-2-(2-(2-nitro-1H-imidazole-1-yl)acetamido)-N-(2-(2-nitro-1H-imidazole-1-yl)ethyl)propenamide (I-Tyr-05) containing two 2-nitroimidazole groups was modified from phenolic hydroxyl to methoxy to 2-(2-methoxyethoxy)ethoxy, gradually achieving improved membrane permeability and enhanced hydrophilicity. Compared with other compounds with similar structures but containing only one 2-nitroimidazole, it had higher hypoxic selectivity. In the uptake experiment of HeLa cells that expressed CAIX, [I]-N-(3-(3-iodo-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1-((2-(2-nitro-1H-imidazole-1-yl)ethyl)amino)-1-oxopropan-2-yl)-4-sulfamoylbenzamide (I-Tyr-06), which contained both 2-nitroimidazole and benzenesulfonamide group, achieved enhanced hypoxic uptake and selectivity through the combination of two targeting groups. The S180 cell blocking experiments of I-Tyr-05 and I-Tyr-06 showed that the benzenesulfonamide group of the compounds didn't inhibit cellular uptake, and inhibition of cytochrome P450 (CYP450) enzyme had no effect on cellular uptake. In silico ADMET evaluation showed that I-Tyr-05 and I-Tyr-06 possessed acceptable physicochemical and ADMET properties. In conclusion, this work demonstrated the advantages of hypoxia-targeted drugs containing dual bioactive groups compared to a single group, and also found it was a feasible approach to design new dual-targeted drugs by combining 2-nitroimidazole and benzenesulfonamide groups.

Over the past two decades, various coronaviruses have posed a severe threat to human life and health, with the spike protein (S protein) being a critical protein for infecting host cells. Glycyrrhizic acid (GA), as a natural drug, can inhibit the infection of coronaviruses by binding to the receptor-binding domain (RBD) of the S protein. However, issues like poor water solubility and weak binding affinity with the S protein have hindered its further application. Therefore, drawing inspiration from the biological structure of centipedes, a ROS-responsive multi-branched drug conjugate (ODPAG) was constructed through a "polymer-drug linkage" strategy using dextran as the backbone and GA as the active "claw". ODPAG exhibited drug loading of 22.0 ± 0.2% (ODPAG) and 19.7 ± 0.1% (ODkPAG), showing ROS responsiveness with a half-life 6.4 times that of GA (ODPAG) and 5.4 times longer (ODkPAG). In in vitro antiviral experiments, ODPAG exhibited an enhanced binding affinity to the S protein, with IC values of 1.33 μM (ODPAG) and 0.89 μM (ODPAG) against SARS-CoV-2 pseudovirus, demonstrating exceptional antiviral efficacy. These results collectively indicate that ODPAG can block coronavirus infection by binding to the S protein, exhibiting significant potential in addressing the current challenges posed by the novel coronavirus. Additionally, the "polymer-drug conjugate" strategy employed in this process is efficient, cost-effective, and offers new insights for combating future emergent coronaviruses.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach in the treatment of chronic HBV infection. In the quest for effective therapeutics against chronic Hepatitis B virus (HBV) infection, we employed a novel binding site occupancy strategy to develop novel 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV CAMs. Our diversity modification approach led to the identification of compound 17e, which demonstrated remarkable anti-HBV activity with an EC of 0.033 μM in HepAD38 cells. Molecular insights obtained through docking and dynamics simulations have provided a comprehensive understanding of the hydrogen bonding interactions between 17e and crucial residues of the HBV core protein, while also revealing the occupation of a novel binding site by the cyclopropyl group, thereby elucidating its inhibitory mechanism. Although 17e exhibited robust metabolic stability in plasma, it underwent rapid metabolism in human liver microsomes. This study underscores the potential of CP-TBA derivatives in crafting the next generation of HBV CAMs with enhanced activity and druggability.

Allergic rhinitis (AR) is a non-infectious inflammatory disease and affects nearly half of the world's population currently, thus becoming a global health problem. In our study, a series of 1,2,4-triazole enamides were designed and used to evaluate the anti-inflammatory activity of AR. We found that compound 11g could significantly reduce the increased expression of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in Raw264.7 cells induced by lipopolysaccharides (LPS), and inhibit the expression of inflammation through MAPK pathway and NF-κB pathway by influencing the expression of cannabinoid-1 receptor (CB1 R). In the AR mice model, 11g can significantly reduce the number of inflammatory cells in Nasal lavage fluids (NLF), showing a good effect on the treatment of AR. This study provides a new and effective candidate for treatment of AR.

The increasing prevalence of antibiotic-resistant Gram-negative bacteria necessitates the development of novel antimicrobial agents with targeted specificity. In this study, we designed and optimized derivatives of the antimicrobial peptide AA16, which truncated from CD14 protein α-helical region, to selectively target Gram-negative bacteria by enhancing lipopolysaccharide (LPS)-enriched interactions, thereby achieving antibacterial spectrum conversion. Starting from the parent peptide AA16 (Ac-AARIPSRILFGALRVL-Amide), we performed strategic amino acid substitutions based on structure-activity relationship analysis. This led to the identification of AA16-10R, a derivative with a specific substitution at position 10, which demonstrated significantly enhanced antibacterial activity against Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa, while maintaining low hemolytic activity. Mechanistic studies revealed that AA16-10R exhibited a strong binding affinity to LPS (K = 0.15 μM), and its interaction with LPS induced the formation of an α-helical structure. This conformational change facilitated its accumulation on the bacterial outer membrane and disrupted membrane integrity. Our innovative approach of exploiting LPS-enriched interactions successfully converted the antimicrobial spectrum of AA16 derivatives from broad-spectrum to Gram-negative-specific. This study highlights a novel strategy for the rational design of antimicrobial peptides based on specific protein-protein interactions, offering a promising avenue for targeted antimicrobial therapy against Gram-negative pathogens.

To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the "tolerant region I″ and "tolerant region II" of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, 13a was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC values ranging from 0.0062 to 0.25 μM, being superior to that of efavirenz (EFV, EC = 0.0080-0.37 μM). In addition, 13a was proved to have low cytotoxicity (CC = 160.7 μM) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that 13a is a classical NNRTI with an IC value of 0.41 μM. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of 13a as a promising lead for the development of the new generation HIV-1 NNRTIs drugs.

Fat mass and obesity-associated protein (FTO) is the first discovered RNA N-methyladenosine (mA) demethylase. The highly expressed FTO protein is required to trigger oncogenic pathways in acute myeloid leukemia (AML), which makes FTO a promising antileukemia drug target. In this study, we identify 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors with good antileukemia activity. We replaced the phenyl A-ring in FB23, the first-generation of FTO inhibitor, with five-membered heterocycles and synthesized a new class of FTO inhibitors. Compound 12o/F97 shows strong enzymatic inhibitory activity and potent antiproliferative activity. 12o/F97 selectively inhibits mA demethylation by FTO rather than ALKBH5, and has minimal effect on mA demethylation by ALKBH3. Additionally, 12o/F97 increases the protein levels of RARA and ASB2, while decreasing that of MYC in AML cell lines. Lastly, 12o/F97 exhibits antileukemia activity in a xenograft mice model without significant side-effects. The identification of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors not only expands the chemical space but also holds potential for antileukemia drug development.

P2YR is activated by UDP (uridine diphosphate) and UDP glucose and associated with the development of many inflammatory diseases. P2YR antagonists are expected to be a new choice for the treatment of inflammatory diseases. A DNA-encoded chemical library (DEL) of 4 billion molecules was screened, leading to the identification of compound A, a novel benzisoxazole scaffold-based P2Y antagonist with an IC value of 23.60 nM. Binding mode analysis and SPR analysis (KD = 7.26 μM) demonstrated that Compound A bind strongly to P2YR. ‌Molecular dynamics simulations and binding free energy calculations were performed to analyze the binding mode of Compound A with P2YR. And in the LPS-induced acute lung injury mice, after treatment with Compound A, the degree of lung injury was greatly reduced, the infiltration of immune cells was decreased, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased. Compound A exhibited good P2YR antagonist activity, demonstrated efficacy both in vitro and in vivo, possessed favorable druggability, and featured a novel benzisoxazole scaffold with potential for further optimization, providing a new strategy for developing subsequent P2Y14 antagonists.

Parkinson's Disease (PD) is characterized by the pathological aggregation of α-synuclein (αSyn) into oligomers and amyloid fibrils, making αSyn aggregation a key target for drug development. Peptides have gained recent attention as potential agents to inhibit aggregation. Two previously identified peptide inhibitors, discovered through large-scale yeast screening, were used as templates for in silico mutagenesis aimed at designing novel peptides with improved efficacy in inhibiting αSyn aggregation and cytotoxicity. The newly designed peptides underwent in silico docking analysis, and the most promising candidates were tested in vitro and in cellular models. Peptides T02 and T05 emerged as the most effective inhibitors, with T02 binding αSyn monomers and T05 targeting lower-order oligomers. Both peptides reduce αSyn fibril and oligomer formation in vitro and significantly suppress αSyn aggregation and cytotoxicity in yeast and human H4 cells. These novel peptides represent antagonists of αSyn aggregation with promising potential for therapeutic intervention for PD.

Acute lung injury (ALI) and ulcerative colitis (UC) are common inflammatory diseases with high mortality rates and unsatisfactory cure rates. Studies have indicated that inhibiting the expression and release of inflammatory factors holds potential for the treatment of inflammatory diseases. In this study, we designed and synthesized 28 derivatives of 6,7-disubstituted-4-cis-cyclohexanequinazoline and assessed their anti-inflammatory activities in mouse macrophages RAW264.7, J774A.1, and human monocyte THP-1 cell lines. Among them, derivative c1 was found to significantly inhibit the expression and release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) induced by lipopolysaccharide (LPS) in the three cells mentioned above. It was also demonstrated that c1 could bind to IRAK4 and affect the expression of these two inflammatory factors by inhibiting the activation of the MAPK pathway. Furthermore, in vivo experiments revealed that c1 effectively ameliorated LPS-induced ALI and dextran sulfate sodium (DSS)-induced UC. Additionally, we evaluated the pharmacokinetic properties and in vivo safety of c1. Therefore, our research has identified the 6,7-disubstituted-4-cis-cyclohexanequinazoline derivative c1 exhibiting promising anti-inflammatory effects as a prospective anti-inflammatory drug candidate.