T5S1607 identified as a antibacterial FtsZ inhibitor：Virtual screening combined with bioactivity evaluation for the drug discovery.

Due to antibiotic overuse, many bacteria have developed resistance, creating an urgent need for novel antimicrobial agents. It has been established that the filamentous temperature-sensitive mutant Z (FtsZ) of the bacterial cell division protein is an effective and promising antibacterial target. In this study, the optimal proteins were assessed by early recognition ability and the processed compound libraries were virtually screened using Vina. This effort resulted in the identification of 14 potentially active antimicrobial compounds. Among them, the compound T5S1607 demonstrated remarkable antibacterial efficacy against Bacillus subtilis ATCC9732 (MIC = 1 µg/mL) and Staphylococcus aureus ATC5C6538 (MIC = 4 µg/mL). Furthermore, in vitro experiments demonstrated that the selected compound T5S1607 rapidly killed bacteria and induced FtsZ protein aggregation, preventing bacterial division and leading to bacterial death. Additionally, cell toxicity and hemolysis experiments indicate that compound T5S1607 exhibits minimal toxicity to LO2 cells and shows no significant hemolytic effects on mammalian cells in vitro at the MIC concentration range. All the results indicate that compound T5S1607 is a promising antibacterial agent and a potential FtsZ inhibitor. In conclusion, this work successfully discovered FtsZ inhibitors with good activity through the virtual screening drug discovery process.

Thiazole-based analogues as potential antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) and their SAR elucidation.

In recent years, the overuse of antibiotics has resulted in the emergence of antibiotic resistance, which is a serious global health problem. Methicillin-resistant Staphylococcus aureus (MRSA) is a common and virulent bacterium in clinical practice. Numerous researchers have focused on developing new candidate drugs that are effective, less toxic, and can overcome MRSA resistance. Thiazole derivatives have been found to exhibit antibacterial activity against drug-sensitive and drug-resistant pathogens. By hybridizing thiazole with other antibacterial pharmacophores, it is possible to obtain more effective antibacterial candidate drugs. Thiazole derivatives have shown potential in developing new drugs that can overcome drug resistance, reduce toxicity, and improve pharmacokinetic characteristics. This article reviews the recent progress of thiazole compounds as potential antibacterial compounds and examines the structure-activity relationship (SAR) in various directions. It covers articles published from 2018 to 2023, providing a comprehensive platform to plan and develop new thiazole-based small MRSA growth inhibitors with minimal side effects.

Fisetin treatment alleviates kidney injury in mice with diabetes-exacerbated atherosclerosis through inhibiting CD36/fibrosis pathway.

Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR-/-) mice. Diabetes was induced in LDLR-/- mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor ß (TGFß)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent for the treatment of renal injury caused by diabetes and atherosclerosis. We reveal that fisetin is an inhibitor of CD36 for reducing the progression of kidney fibrosis, and fisetin-regulated CD36 may be a therapeutic target for the treatment of renal fibrosis.

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives.

Factor XIa (FXIa) in the intrinsic pathway of the coagulation process has been proven to be an effective and safe target for anticoagulant discovery with limited or no bleeding. Numerous small-molecule FXIa inhibitors (SMFIs) with various scaffolds have been identified in the early stages of drug discovery. They have served as the foundation for the recent discovery of additional promising SMFIs with improved potency, selectivity, and pharmacokinetic profiles, some of which have entered clinical trials for the treatment of thrombosis. After reviewing the coagulation process and structure of FXIa, this perspective discusses the rational or structure-based design, discovery, structure-activity relationships, and development of SMFIs disclosed in recent years. Strategies for identifying more selective and druggable SMFIs are provided, paving the way for the design and discovery of more useful SMFIs for anticoagulation therapy.

Roxadustat alleviates nitroglycerin-induced migraine in mice by regulating HIF-1α/NF-κB/inflammation pathway.

Sensitization of central pain and inflammatory pathways play essential roles in migraine, a primary neurobiological headache disorder. Since hypoxia-inducible factor-1α (HIF-1α) is implicated in neuroprotection and inflammation inhibition, herein we investigated the role of HIF-1α in migraine. A chronic migraine model was established in mice by repeated injection of nitroglycerin (10 mg/kg, i.p.) every other day for 5 total injections. In the prevention and acute experiments, roxadustat, a HIF-1α stabilizer, was orally administered starting before or after nitroglycerin injection, respectively. Pressure application measurement, and tail flick and light-aversive behaviour tests were performed to determine the pressure pain threshold, thermal nociceptive sensitivity and migraine-related light sensitivity. At the end of experiments, mouse serum samples and brain tissues were collected for analyses. We showed that roxadustat administration significantly attenuated nitroglycerin-induced basal hypersensitivity and acute hyperalgesia by improving central sensitization. Roxadustat administration also decreased inflammatory cytokine levels in serum and trigeminal nucleus caudalis (TNC) through NF-κB pathway. Consistent with the in vivo results showing that roxadustat inhibited microglia activation, roxadustat (2, 10, and 20 µM) dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway. Taken together, this study demonstrates that roxadustat administration ameliorates migraine-like behaviours and inhibits central pain sensitization in nitroglycerin-injected mice, which is mainly mediated by HIF-1α/NF-κB/inflammation pathway, suggesting the potential of HIF-1α activators as therapeutics for migraine.

Discovery of Polo-like Kinase 4 Inhibitors for the Treatment of Cancer: A Mini Patent Review.

Polo-like kinase 4 (PLK4), a serine/threonine kinase, is a member of the PLK family. As a key regulator of the cell cycle, PLK4 controls centrosome duplication and mitosis. Abnormal PLK4's function can induce centrosome amplification, leading to tumorigenesis, therefore, PLK4 has been regarded as a promising target for cancer therapy, and PLK4 inhibitors have potentials to treat multiple cancers and other PLK4-associated human disorders, such as myelodysplastic syndrome. In addition, PLK4 may function as a DNA-damage sensitizer, therefore improving the efficacy of chemotherapy. To date, some small-molecule inhibitors with different chemical scaffolds targeting PLK4 have been reported, among which, CFI-400945 has entered clinical trials for the treatment of various solid tumors, myeloid leukemia, and myelodysplastic syndrome. In this review, the structure and biological functions of PLK4 with other homologous PLKs are compared; the roles of PLK4 in different cancers are reviewed; and PLK4 inhibitors disclosed in patent or literature are summarized. Used alone or in combination with other anticancer drugs in preclinical and clinical studies, PLK4 inhibitors have shown significant efficacy in the treatment of different cancers, demonstrating that PLK4 could be a critical target for cancer diagnosis and therapy. However, our understanding of PLK4 is still limited, and novel mechanisms of PLK4 should be identified in future studies.

Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts.

Inhibition of cyclin-dependent kinases (CDKs) has become an effective therapeutic strategy for treating various diseases, especially cancer. Over almost three decades, although great efforts have been made to discover CDK inhibitors, many of which have entered clinical trials, only four CDK inhibitors have been approved. In the process of CDK inhibitor development, many difficulties and misunderstandings have hampered their discovery and clinical applications, which mainly include inadequate understanding of the biological functions of CDKs, less attention paid to pan- and multi-CDK inhibitors, nonideal isoform selectivity of developed selective CDK inhibitors, overlooking the metabolic stability of early discovered CDK inhibitors, no effective resistance solutions, and a lack of available combination therapy and effective biomarkers for CDK therapies. After reviewing the mechanisms of CDKs and the research progress of CDK inhibitors, this perspective summarizes and discusses these difficulties or lessons, hoping to facilitate the successful discovery of more useful CDK inhibitors.

Targeting the S2 Subsite Enables the Structure-Based Discovery of Novel Highly Selective Factor XIa Inhibitors.

FXIa inhibition has been a promising strategy for treating thrombotic diseases. Up to date, many small-molecule FXIa inhibitors have been identified; however, most of them exhibit undesirable selectivity over the homologous plasma kallikrein (PKal). By employing structure-based drug design strategies, we identified many novel selective FXIa inhibitors that have extra interactions with the S2 subsite of FXIa. Among them, compound 35 displayed good inhibitory activity against FXIa and high selectivity over PKal and even several other serine proteases. Additionally, 35 showed significant anticoagulant activity toward the intrinsic pathway without affecting the extrinsic pathway. In vivo, 35 exhibited significant antithrombotic activity without increasing the bleeding risk and obvious toxicity in mice, demonstrating that it could be a promising candidate for further research. This study first demonstrates the importance of the S2 subsite of FXIa, paving the way to design highly selective FXIa inhibitors for clinical uses.

Zinc enzymes in medicinal chemistry.

In humans, more than three hundred diverse enzymes that require zinc as an essential cofactor have been identified. These zinc enzymes have demonstrated different and important physiological functions and some of them have been considered as valuable therapeutic targets for drug discovery. Indeed, many drugs targeting a few zinc enzymes have been marketed to treat a variety of diseases. This review discusses drug discovery and drug development based on a dozen of zinc enzymes, including their biological functions and pathogenic roles, their best in class inhibitors (and clinical trial data when available), coordination and binding modes of representative inhibitors, and their implications for further drug design. The opportunities and challenges in developing zinc enzyme inhibitors for the treatment of human disorders are highlighted, too.

Novel 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as potent selective human monoamine oxidase B inhibitors: Design, SAR development, and biological evaluation.

Successes have been achieved in developing human monoamine oxidase B (hMAO-B) inhibitors as anti-Parkinson's disease (PD) drugs. However, low efficiency and unwanted side effects of the marketed hMAO-B inhibitors hamper their medical applications, therefore, novel potent selective hMAO-B inhibitors are still of great interest. Herein we report 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as hMAO-B inhibitors, which were designed by employing a fragment-based drug design strategy to link rasagiline to hydrophobic fragments. Among the synthesized 31 compounds, K8 and K24 demonstrated very encouraging hMAO-B inhibitory activities and selectivity over hMAO-A, better than rasagiline and safinamide. In vitro studies indicated that K8 and K24 are nontoxic to nervous tissue cells and they have considerable effects against ROS formation and potential neuroprotective activity. Further mice behavioral tests demonstrated these two compounds have good therapeutic effects on MPTP-induced PD model mice. All these experiment results suggest that compounds K8 and K24 can be promising candidates for further research for treatment of PD.

Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases.

Great successes have been achieved in developing small-molecule kinase inhibitors as anticancer therapeutic agents. However, kinase deregulation plays essential roles not only in cancer but also in almost all major disease areas. Accumulating evidence has revealed that kinases are promising drug targets for different diseases, including cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system disorders, viral infections, and malaria. Indeed, the first small-molecule kinase inhibitor for treatment of a nononcologic disease was approved in 2011 by the U.S. FDA. To date, 10 such inhibitors have been approved, and more are in clinical trials for applications other than cancer. This Perspective discusses a number of kinases and their small-molecule inhibitors for the treatment of diseases in nononcologic therapeutic fields. The opportunities and challenges in developing such inhibitors are also highlighted.

Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors.

Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamide, a series of novel 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid derivatives were designed and synthesized. All efforts led to a good dual PARP-1/HDAC-1 inhibitor, compound 4, with IC50 values of 4.2 and 340 nM against PARP-1 and HDAC-1, which were as potent as olaparib and chidamide respectively. The MTT assay further demonstrated that compound 4 had potent inhibitory activities against BRCA1/2-proficient K562 and MDA-MB-231 cells with GI50 values of 5.6 and 4.3 µM, respectively. Therefore, our results suggested that compound 4 could be a promising dual PARP-1/HDAC-1 inhibitor for further studies. In addition, a few excellent PARP-1 inhibitors such as 7-9 and HDAC-1 inhibitors such as 12 were serendipitously discovered, which also could be further studied in our next work.

Discovery and development of plasma kallikrein inhibitors for multiple diseases.

Plasma kallikrein (PKal) belongs to the family of trypsin-like serine proteases. The expression of PKal is associated with multiple physiological systems or pathways such as coagulation pathway, platelet aggregation process, kallikrein-kinin system, renin-angiotensin system and complement pathway. On the basis of PKal's multiple physiological functions, it has been considered as a potential target for several diseases including hereditary angioedema, microvascular complications of diabetes mellitus and cerebrovascular disease. Up to now, many PKal inhibitors have been identified and a few of them have reached clinical trials or market. This review summarizes the development of small molecule and peptide PKal inhibitors having different scaffolds and discusses their structure-activity relationship and selectivity. We hope this review facilitates a comprehensive understanding of the types of PKal inhibitors developed to tackle different manifestations of PKal-associated diseases.

Discovery and Development of Cyclin-Dependent Kinase 8 Inhibitors.

Cyclin-dependent Kinase 8 (CDK8), a member of the CDKs family, has been widely focused owing to investigations of its critical roles in transcription and oncogenesis in recent years. Selective inhibition of CDK8 and its paralog CDK19 offers a novel therapeutic strategy for the treatment of some cancers. Up to now, though many small molecules against CDK8 have been discovered, most of them are discontinued in the preclinical trials due to the low selectivity and poor physicochemical properties. This review mainly summarizes the design strategies of selective CDK8 inhibitors having different chemical scaffolds with the aim to improve the inhibitory activity, selectivity, metabolic stability and solubility. Their corresponding Structure-activity Relationships (SAR) are also reviewed. On the basis of the discussion in this review, we hope more effective, selective and drug-like CDK8 inhibitors will be developed and demonstrate therapeutic values in the near future.

LongShengZhi capsule inhibits doxorubicin-induced heart failure by anti-oxidative stress.

Heart failure is a major cause of morbidity and mortality worldwide. LongShengZhi capsule (LSZ), a traditional Chinese medicine, is used for treatment of patients with vascular diseases. Herein we investigated the effect of LSZ treatment on doxorubicin (DOX)-induced heart failure in mice. C57BL/6 mice randomly in 3 groups received following treatment: Control group, mice were fed normal chow; DOX group, mice were intraperitoneally injected DOX to induce heart failure and fed normal chow; and LSZ group, mice were injected DOX and fed normal chow containing LSZ. DOX induced heart failure as evidenced by increased serum creatine kinase, lactic dehydrogenase and α-hydroxybutyrate dehydrogenase, and cardiac fibrosis. However, LSZ treatment substantially inhibited DOX-induced heart failure parameters. Mechanistically, LSZ reduced collagen content and fibrosis by inhibiting expression of collagen type I α1 (COL1α1), COL1α2, α-smooth muscle actin and transforming growth factor ß1. In addition, DOX-induced cell apoptosis was inhibited by LSZ, coupled with reduced caspase 3 activity and mRNA expression. LSZ decreased inflammatory cytokine levels. More importantly, LSZ decreased oxidative stress by inducing expression of anti-oxidative stress enzymes including superoxide dismutase 1 (SOD1), SOD2, catalase and glutathione peroxidase 1 through activation of forkhead box O3A and sirtuin 3. In conclusion, our study demonstrates that LSZ reduces heart failure by reducing production of reactive oxygen species and inhibiting inflammation/apoptosis. Our study also suggests the potential application of LSZ for heart failure treatment.

Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold.

Polo-like kinase 1 (Plk1) is a validated target for the treatment of cancer. In this report, by analyzing amino acid residue differences among the ATP-binding pockets of Plk1, Plk2 and Plk3, novel selective Plk1 inhibitors were designed based on BI 2536 and BI 6727, two Plk1 inhibitors in clinical studies for cancer treatments. The Plk1 inhibitors reported herein have more potent inhibition against Plk1 and better isoform selectivity in the Plk family than these two lead compounds. In addition, by introducing a hydroxyl group, our compounds have significantly improved solubility and may target specific polar residues Arg57, Glu69 and Arg134 of Plk1. Moreover, most of our compounds exhibited antitumor activities in the nanomolar range against several cancer cell lines in the MTT assay. Through this structure-based design strategy and SAR study, a few promising selective Plk1 inhibitors having the tetrahydropteridin scaffold, for example, L34, were identified and could be for further anticancer research.

Developments in inhibiting platelet aggregation based on different design strategies.

Platelet aggregation is the central event in hemostasis and thrombosis. Up to now, many agents inhibiting platelet aggregation have been approved for the treatment of thrombotic disorders. In this review, we mainly summarized the progress in the research of platelet aggregation inhibitors based on different design strategies. The advantage and challenge of corresponding targets are also discussed in this article. We hope more platelet aggregation inhibitors with efficacy and safety will be discovered in the future.

Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors.

Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson's disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC50 = 0.11 µM), L8 (IC50 = 0.18 µM), L16 (IC50 = 0.27 µM) and L17 (IC50 = 0.48 µM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.

Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure.

Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.