In our previous study, a screening of a variety of lycotonine-type diterpenoid alkaloids were screened for cardiotonic activity revealed that lycoctonine had moderate cardiac effect. In this study, a series of structurally diverse of lycoctonine were synthesized by modifying on B-ring, D-ring, E-ring, F-ring, N-atom or salt formation on lycoctonine skeleton. We evaluated the cardiotonic activity of the derivatives by isolated frog heart, aiming to identify some compounds with significantly enhanced cardiac effects, among which compound 27 with a N-isobutyl group emerged as the most promising cardiotonic candidate. Furthermore, the cardiotonic mechanism of compound 27 was preliminarily investigated. The result suggested that the cardiotonic effect of compound 27 is related to calcium channels. Patch clamp technique confirmed that the compound 27 had inhibitory effects on Ca_V1.2 and Ca_V3.2, with inhibition rates of 78.52 % ± 2.26 % and 79.05 % ± 1.59 % at the concentration of 50 μM, respectively. Subsequently, the protective effect of 27 on H9c2 cells injury induced by cobalt chloride was tested. In addition, compound 27 can alleviate CoCl₂-induced myocardial injury by alleviating calcium overload. These findings suggest that compound 27 was a new structural derived from lycoctonine, which may serve as a new lead compound for the treatment of heart failure.

26 Jan 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa

Q1 · MEDICINE

Article

Author: Fulgheri, Federica ; Tomašič, Tihomir ; Cao, Sha ; Maxwell, Anthony ; Birnir, Bryndis ; Vicente, Francisca ; Ilaš, Janez ; Kikelj, Danijel ; Glinghammar, Björn ; Lenhammar, Lena ; Korol, Sergiy V. ; Zega, Anamarija ; Giachou, Paraskevi ; Crone, Lisa ; Hughes, Diarmaid ; Lawson, David M. ; Simoff, Ivailo ; Mundy, Julia E. A. ; Jin, Zhe ; Garoff, Linnéa ; Sterle, Maša ; Secci, Daniela ; Stevenson, Clare E. M. ; Zidar, Nace ; Ramos, Maria C. ; Janssen, Guido V. ; Skok, Žiga ; de la Cruz, Mercedes ; Sterk, Geert Jan ; Možina, Štefan ; Berruga Fernández, Talía ; Peterlin Mašič, Lucija ; Henderson, Sara R. ; Svensson, Richard ; Durcik, Martina ; Cotman, Andrej Emanuel ; Huseby, Douglas L. ; Benedetto Tiz, Davide

We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

100 Deals associated with Compound 27(University of Ljubljana)

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Indication	Highest Phase	Country/Location	Organization	Date
Acinetobacter Baumannii Infection	Preclinical	Slovenia	University of Ljubljana	12 Jan 2023
Pseudomonas aeruginosa infection	Preclinical	Slovenia	University of Ljubljana	12 Jan 2023

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Compound 27(University of Ljubljana)

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