Aim: Because of the severe morbidity and mortality of gastric cancer, discovering new candidate drugs has been an urgent issue. The close association between histone deacetylase 6 (HDAC6) and gastric cancer makes the development of HDAC6-targeted anti-gastric cancer drugs a viable idea. Methods & results: Carbenoxolone disodium was identified as a novel HDAC6 inhibitor. Cellular thermal shift assay, surface plasmon resonance assay and molecular docking confirmed its binding ability to HDAC6. Cell viability, wound healing and transwell assays as well as animal studies have demonstrated that carbenoxolone disodium could block the proliferation and migration of gastric cancer cells MGC-803 in vitro and in vivo. Conclusion: This is the first report to indicate that carbenoxolone disodium could be an HDAC6 inhibitor with potential for treatment of gastric cancer.

Sulfonamides are privileged candidates with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and could replenish the MRSA antibiotic pipeline. The initial screening of a series of quinazolinone benzenesulfonamide derivatives 5-18 against multidrug-resistant bacterial and fungal strains revealed their potent activity. The promising compounds were conjugated with ZnONPs to study the effect of nanoparticle formation on the antimicrobial, cytotoxic and immunomodulatory activity. Compounds 5, 11, 16 and 18 revealed promising antimicrobial and cytotoxic activities with superior safety profiles and enhanced activity upon nanoformulation. The immunomodulatory potential of compounds 5, 11, 16 and 18 was assessed. Compounds 5 and 11 demonstrated an increase in spleen and thymus weight and boosted the activation of CD4+ and CD8+ T lymphocytes, confirming their promising antimicrobial, cytotoxic and immunomodulatory activity.

Background: Identification of molecules having dual capabilities to reduce postprandial hyperglycemia and oxidative stress is one of the therapeutic approaches to treat diabetes mellitus. In this connection, a library of benzofuran-linked chalcone derivatives were evaluated for their dual action. Methods: A series of substituted benzofuran-linked chalcones (2-33) were synthesized and tested for α-amylase inhibitory as well as 2,2-diphenylpicrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities. Results: All compounds showed α-amylase inhibitory activity ranging from IC50 = 12.81 ± 0.03 to 87.17 ± 0.15 μM, compared with the standard acarbose (IC50 = 13.98 ± 0.03 μM). Compounds also demonstrated radical scavenging potential against DPPH and ABTS radicals. Conclusion: The identified compounds may serve as potential leads for further advanced research.

Aim: To develop an efficient and cost-effective antidiabetic agent. Methods: A simple and convenient Hantzsch synthetic strategy was used to prepare 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles. Results: Fifteen newly established structures of 4-adamantyl-(2-(arylidene)hydrazinyl)thiazoles were tested for their α-amylase, antiglycation and antioxidant activities. Almost all tested compounds showed excellent α-amylase inhibition. Compounds 3a and 3j exhibited the highest potency, with IC50 values of 16.34 ± 2.67 and 16.64 ± 1.12 μM, respectively. Compounds 3c and 3i exhibited comparable antiglycation potential with the standard, aminoguanidine. The antioxidant potential of compound 3g was found to be excellent, with an IC50 value of 28.19 ± 0.2563 μM. The binding interactions of compound 3a (binding energy = -8.833 kcal/mol) with human pancreatic α-amylase identified 3a as a potent α-amylase inhibitor. Conclusion: Enrichment of established structures with more electron-donating functionalities may assist/lead to the development of more potent antidiabetic drugs.

Aim: To identify novel inhibitors of SIRT1 and to understand their mechanism of action in hepatocellular carcinoma. Materials & methods: Molecular docking and dynamic simulations were conducted to identify potential SIRT1 inhibitors. The in vitro efficacy of the inhibitors was evaluated by methyl thiazolyl tetrazolium assays, flow cytometry and western blot analysis. Additionally, the in vivo antitumor activity of the inhibitor was evaluated. Results: Tipranavir, a US FDA-approved anti-HIV-1 medication, was found to possess potential as a SIRT1 inhibitor. Tipranavir selectively inhibited HepG2 cell proliferation without causing toxicity to normal human hepatic cells. Additionally, tipranavir treatment resulted in a reduction of SIRT1 expression and induction of apoptosis in HepG2 cells. Furthermore, tipranavir was found to suppress tumorigenesis in a xenograft mouse model and decreased the expression of SIRT1 in vivo. Conclusion: Tipranavir holds desirable potential as a promising therapeutic agent against hepatoma.

HDAC8 catalyzes the deacetylation of both histones and nonhistone proteins. The abnormal expression of HDAC8 is associated with various pathological conditions causing cancer and other diseases like myopathies, Cornelia de Lange syndrome, renal fibrosis, and viral and parasitic infections. The substrates of HDAC8 are involved in diverse molecular mechanisms of cancer such as cell proliferation, invasion, metastasis and drug resistance. Based on the crystal structures and the key residues at the active site, HDAC8 inhibitors have been designed along the canonical pharmacophore. This article details the importance, recent advancements, and the structural and functional aspects of HDAC8 with special emphasis on the medicinal chemistry aspect of HDAC8 inhibitors that will help in developing novel epigenetic therapeutics.

Aim: To test the antimicrobial effect of carbon monoxide-releasing molecules (CORMs) conjugated with azoles on different microorganisms. Methods & results: We used broth microdilution, checkerboard and cytotoxicity assays, as well as imaging, fluorescence and bioluminescence experiments to study [Re(CO)3(2,2'-bipyridyl)(Ctz)]+ (also known as ReBpyCtz). ReBpyCtz exhibits a low minimum inhibitory concentration value, increases the intracellular formation of reactive oxygen species and causes significant alterations on Staphylococcus aureus's membrane. ReBpyCtz is active against fungi, having a more prolonged fungicidal effect on Candida glabrata than clotrimazole and is selectively active on blood-stage malaria parasites, at a concentration that is not toxic to kidney epithelial cells. Conclusion: Conjugated CORMs have the potential to be active against different types of pathogens, thus constituting a promising class of broad-spectrum antimicrobials.

Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 Mpro with IC50 values of 0.4-3 μM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 Mpro inhibitors.

Aim: The oleanolic acid derivatives containing electrophilic warheads were synthesized, and their antitumor activities were investigated. Materials & methods: The cytotoxicity of compounds against tumor cells were determined by the MTT method. The antitumor effects of compounds 27a, Y03 and Y04 were evaluated in vitro through a wound-healing assay, apoptosis and cell circle analysis, and cellular reactive oxide species determination. The levels of related proteins in MCF-7 cells treated with Y03 was determined through Western blot analysis. Results & conclusion: Compounds 27a, Y03 and Y04 displayed high cytotoxicity against breast cancer cells and inhibited cell migration, induced apoptosis, arrest cell circle at G0/G1 and promoted cellular reactive oxide species generation. The antitumor mechanism involved inhibition of Akt/mTOR and induction of ferroptosis.

Diabetic retinopathy and age-related macular degeneration are common retinal diseases with shared pathophysiology, including oxidative stress-induced inflammation. Cellular mechanisms responsible for converting oxidative stress into retinal damage are ill-defined but have begun to clarify. One common outcome of retinal oxidative stress is mitochondrial damage and subsequent release of mitochondrial DNA into the cytosol. This leads to activation of the cGAS-STING pathway, resulting in interferon release and disease-amplifying inflammation. This review summarizes the evolving link between aberrant cGAS-STING signaling and inflammation in common retinal diseases and provides prospective for targeting this system in diabetic retinopathy and age-related macular degeneration. Further defining the roles of this system in the retina is expected to reveal new disease pathology and novel therapeutic approaches.

HIPK2 is a serine/threonine kinase, located in the nucleus, that was initially found to be able to phosphorylate p53 at Ser46 to promote apoptosis; it has been widely studied. It has been reported that HIPK2 can simultaneously regulate TGF-β/Smad3, Wnt/β-catenin, Notch and NF-κB pathways in the kidney to initiate inflammation and fibrosis, resulting in the development of chronic kidney disease (CKD). Therefore, inhibition of HIPK2 is strongly considered an effective method for the treatment of CKD. In brief, this review summarizes the progress of HIPK2 in CKD as well as the reported HIPK2 inhibitors and their role in different CKD models.

Aim: To develop and evaluate chitosan-maleic acid conjugate. Methods: Maleic anhydride was attached to chitosan backbone via amide bond formation resulting in chitosan-maleic acid. After characterization of the product via 1H nuclear magnetic resonance, attenuated total reflectance-Fourier transform IR spectroscopy and 2,4,6-trinitrobenzenesulfonic acid assay, examination of mucoadhesion assessment was carried out. Results: The conjugate presented 44.91% modification and no toxicity could be observed after 1 day of incubation. Mucoadhesive properties exhibited 40.97-fold, 13.31-fold and 9.07-fold increase in elastic modulus, dynamic viscosity and viscous modulus, respectively. Moreover, detachment time was increased in 44.44-fold. Conclusion: Chitosan-maleic acid demonstrated enhanced in mucoadhesive properties resulting in biocompatibility. Therefore, potent candidates as polymeric excipients for oral drug delivery could be developed over corresponding chitosan.

Background: Sepsis is a syndrome due to microbial infection causing impaired multiorgan function. Its underlying cause is immune dysfunction and macrophages play an essential role. Methods: TIRAP interaction with PKCδ in macrophage was studied, revealing downstream signaling by Western blot and quantitative reverse transcriptase PCR. Dorzolamide (DZD) disrupting TIRAP-PKCδ interaction was identified by virtual screening and validated in vitro and in septic mice. Results: The study highlights the indispensable role of TIRAP-PKCδ in p38 MAPK-activation, NF-κB- and AP-1-mediated proinflammatory cytokines expression, whereas DZD significantly attenuated the signaling. Conclusion: Targeting TIRAP-PKCδ interaction by DZD is a novel therapeutic approach for treating sepsis.

Aim: In this study, novel hybrid structures of pyrimido-indole-oxadiazole were developed as MDM2 inhibitors for restoring the regular function of the p53. Materials & methods: A multistep chemical pathway was used to synthesize the derivatives. Nutlin-3a was used as a standard lead in molecular docking and molecular dynamics simulations. Finally, cytotoxicity was evaluated against MCF-7 cancer cells versus Doxorubicin. Results: The most promising candidate was 12c, which had an NO2 group in the para position of the oxadiazole ring (IC50: 1.1 μM). A satisfactory result was obtained with the combined application of 12c and Doxorubicin (IC50 decreased to 0.63 μM), which could be potentially attributed to MDM2 inhibition. Conclusion: These hybrid structures can be further investigated as potential MDM2 inhibitors.

Prodrug strategy is critical for innovative drug development. Structural modification is the most straightforward and effective method to develop prodrugs. Improving drug defects and optimizing the physical and chemical properties of a drug, such as lipophilicity and water solubility, changing the way of administration can be achieved through specific structural modification. Designing prodrugs by linking microenvironment-responsive groups to the prototype drugs is of great help in enhancing drug targeting. In the meantime, making connections between prodrugs and suitable drug delivery systems could realize drug loading increases, greater stability, bioavailability and drug release control. In this paper, lipidic, water-soluble, pH-responsive, redox-sensitive and enzyme-activatable prodrugs are reviewed on the basis of structural modification.

Background: It has been demonstrated that the lead compound 2-phenylimidazo[1,2-a]quinoline 1a selectively inhibits CYP1 enzymes. Additionally, CYP1 inhibition has been linked to inducing antiproliferative effects in various breast cancer cell lines as well as relieving drug resistance caused by CYP1 upregulation. Materials & methods: Herein, 54 novel analogs of 2-phenylimidazo[1,2-a]quinoline 1a have been synthesized with varied substitution on the phenyl and imidazole rings. Antiproliferative testing was conducted using 3H thymidine uptake assays. Results: 2-Phenylimidazo[1,2-a]quinoline 1a and phenyl-substituted analogs 1c (3-OMe), 1n (2,3-napthalene) displayed excellent anti-proliferative activities, demonstrating their potency against cancer cell lines for the first time. Molecular modeling suggested that 1c and 1n bind similarly to 1a in the CYP1 binding site.