Medicinal Chemistry - Volume 19, Issue 7, 2023

Despite major antimicrobial therapeutic advancements, widespread use and misuse of antimicrobial drugs have increased antimicrobial drug resistance, posing a severe danger to public health. In particular, the emergence of multidrug-resistant bacteria has provided considerable difficulty in the treatment of pathogenic infections. As a result, the creation of novel drugs to treat resistant bacteria is one of the most significant disciplines of antimicrobial research today. TB therapy has recently gained a lot of attention, in addition to developing novel and efficient antibacterial drugs to battle multidrug-resistant illnesses. The use of a different class of drugs, such as well-known drugs, their derivatives, and various new heterocyclic compounds like nitroimidazoles, imidazole analogues, triazoles, imidazopyridines, quinolines, purines, as well as thioactomycin, mefloquine, deazapteridines, benzothiadiazine and other molecules such as benzoxazines, diterpenoids, tryptanthin and phenazine and toluidine analogues followed by many other classes of compounds and their effects are also discussed. As a result, current and newly found antitubercular drugs and their toxicities and mode of action have been focused.

Background: Preclinical studies suggest that senolytic compounds such as quercetin (a natural product) and dasatinib (a synthetic product) decrease senescent cells, reduce inflammation, and alleviate human frailty. This evidence has opened a new field of research for studying the effect of these compounds on age-related dysfunction and diseases. Objective: The present study performed in silico and we identified new potential senolytic candidates from an extensive database that contains natural products (NPs) and semi-synthetic products (SMSs). Methods: Computer programs Chemminer and rcdk packages, which compared the fingerprints of numerous molecules (40,383) with reference senolytics, and the creation of a pharmacological network built with signaling pathways and targets involved in senescence processes were used to identify compounds with a potential activity. Results: Six drug-like candidates (3,4'-dihydroxypropiophenone, baicalein, α, β-dehydrocurvularin, lovastatin, luteolin, and phloretin) were identified. Conclusion: To our knowledge, this is the first time that these six natural molecules have been proposed to have senolytic activity. To validate the methodology employed in the identification of new drug-like senolytics, experimental evidence is needed with models that evaluate senolytic activity.

Background: Chalcones are precursors of flavonoids and exhibit a broad spectrum of pharmacological activity. Objective: As anti-inflammatory agents, two series of chalcone derivatives and chalcone-based oximes were synthesized and characterized. To integrate the tetramethylpyrazine moiety into these novel molecules, the multifunctional natural chemical ligustrazine was employed. Methods: A variety of newly synthesized ligustrazine-based chalcones were utilized as precursors for the synthesis of new oximes and their inhibitory activity against COX-1, COX-2, and LOX-5 enzymes were compared. Results: The conversion of ketones to their oxime derivatives increased the effectiveness of COX-1 and COX-2 inhibition. Due to the substituted ether groups, oxime derivative 5d had the lowest IC50 values of 0.027 ± 0.004 μM and 0.150 ± 0.027 μM for COX-1 and COX-2 isoenzymes, respectively. Notably, the oxime derivative's highest effectiveness is conferred by the presence of methoxymethoxy or hydroxy groups at the C-3 and C-4 positions on the phenyl ring. The 6b derivative with a long alkyl chain ether group was shown to be the most powerful 5-LOX inhibitor. All compounds were also assessed for their ability to inhibit nitric oxide generation and LPS-induced IL-6, IL-1β, and TNF-α production in RAW 264.7 macrophages. Finally, in order to determine the structural effects responsible for the binding mechanism of compounds, they were docked into the binding sites of COX-1, COX-2, and 5-LOX, which revealed an inhibitory mechanism of action and demonstrated the relevance of various types of interactions. Conclusion: The findings showed that these novel compounds had a significant impact on antiinflammatory actions.

Introduction: Based on bioactive group splicing, classical bioisosterism, and the rule of alkene insertion, forty-eight aurone, and indanone derivatives were designed and synthesized. They were evaluated for inhibitory activity against C. albicans, E. coli, and S. aureus. Among them, thirty compounds exhibited moderate to excellent antibacterial activity. Methods: The maximum circle of inhibition was 18 mm (compounds B15, B16, and E7), and the minimum values of MIC and MBC were respectively 15.625 μM (compounds A5 and D2) and 62.5 μM (compounds A6, A8, and E7). Results: The SAR showed that aurone and indanone derivatives could strongly inhibit the growth of Gram-positive bacteria. The introduction of electron-withdrawing groups or hydroxyl is beneficial to the activity. It was exciting that the 3-phenylallylbenzofuranone and 3-allylindanone skeletons with antimicrobial activity were first reported in this study. Compounds A5 and E7 were selected for molecular docking studies with targets MetRS (PBD: 7WPI) and PBP (PDB: 6C3K) to determine the binding interactions at the active site. Conclusion: On this basis, the physicochemical and pharmacological properties of the compounds were predicted and analyzed. The influence of these properties on antimicrobial activity and their implications for subsequent work were discussed. The ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) predictions showed that most of the compounds had good pharmacokinetic profiles and high safety profiles.

Background: Hyperuricemia is closely related to the occurrence of gout, hypertension, diabetes, hyperlipidemia, cardiovascular disease, kidney disease, metabolic syndrome, etc. However, xanthine oxidase inhibitors (XOIs) can fundamentally solve the problem of excessive uric acid. Compared to single-target drugs, multi-target drugs are not prone to adverse reactions and exert a synergistic effect. Therefore, the discovery of new multi-target XOIs and their mechanism of therapeutic hyperuricemia are important to overcome adverse effects and resistance to currently available drugs. Objective: The purpose of this paper is to obtain novel diazine derivatives as promising multi-target XOIs and discover the interaction mechanism for the better treatment of hyperuricemia. Methods: Novel multi-target XOIs diazine derivatives, and their interaction mechanism have been obtained through QSAR, molecular docking, dynamics simulation, and network pharmacology. In addition, ADMET properties and synthetic accessibility of novel XOIs have been considered using ADMETLAB 2.0 and SwissADME. Results: 24 novel diazine derivatives as potential multi-target XOIs lead compounds have been found through virtual screening of the PubChem database. Moreover, the most notable top five compounds are worthy of further developing as multi-target XOIs drugs. XDH, TBK1, DGAT1, MYC, CDKN1A, PPARD, PDE6C, and EIF4E are recommended as relevant targets of therapeutic hyperuricemia. Conclusion: Through the combination of different methods, we have discovered five novel promising diazine derivatives as potential multi-target XOIs drugs. Meanwhile, eight targets have been found to be helpful in the research on therapeutic hyperuricemia. We expect this investigation will offer clear insights into the production of efficient XOIs drugs.