The development of novel 4,10-diazachrysene and 1,5-naphthyridine derivatives as Ebola virus inhibitors

Ebolavirus je rod virusa iz familije Filoviridae, endemski prisutan u Subsaharskoj Africi. Vrste koje pripadaju ovom rodu uzročnici su smrtonosne hemoragijske groznice kod ljudi i primata, a otkrivene su, kao i njima srodni virusi marburga, u drugoj polovini 20. veka, kada su registrovani prvi slučajevi. U ovom trenutku ne postoji odobrena vakcina niti lek protiv ove opasne infekcije. Nekoliko imunoterapeutika, kao i složenih makromolekulskih formulacija, predstavlja obećavajuće kandidate za lek, a ostvaren je i napredak u istraživanjima sa malim molekulima. Oslanjajući se na ranija istraživanja u našoj istraživačkoj grupi, u okviru ove teze sintetisane su dve grupe jedinjenja za koje se pretpostavljalo da mogu imati antivirusnu aktivnost – derivati 4,10-diazahrizena i 1,5-naftiridina. Ukupno je testirano 29 jedinjenja, a po aktivnosti naročito su se istakla dva diazahrizenska derivata koji su imali veoma dobru in vitro aktivnost i štitili su 9/10, odnosno 10/10 inficiranih miševa pri dozi 10 mg/kg. Urađen je veći broj ogleda sa ciljem utvrđivanja mehanizma dejstva ova dva jedinjenja, pri čemu je otkriveno da ona inhibiraju ulazak virusa u ćeliju domaćina, na način koji se razlikuje od do sada poznatih inhibitora ulaska virusa. Dobijeni rezultati ukazuju da su molekuli razvijeni u ovoj tezi značajni i jedinstveni i da zavređuju dalja ispitivanja.Ebolavirus is a genus of viruses from the Filoviridae family, endemic to Sub-Saharan Africa. Species from this genus cause a lethal hemorrhagic fewer in humans and non-human primates. Like the related Marburgviruses, they were discovered in the second half of the 20th century, when first cases were reported. Presently, there is no approved vaccine or other therapeutics to treat this dangerous infection. Several immunotherapeutics, as well as sophisticated macromolecular formulations, have shown promising results, and advances have also been made in small molecule research. Based on our previous results we developed two new chemotypes as possible antivirals – derivatives of 4,10-diazachrysene and 1,5-naphthyridine, respectively. A total of 29 compounds were tested, with two of them showing very good results: they had excellent in vitro activity and they protected 9/10 and 10/10 infected mice from a fatal Ebola challenge, respectively (10 mg/kg dose). A number of experiments were carried out to determine the mechanism of action of these two compounds, and it was discovered that they prevent viral entry into cells, albeit in a manner that differed from other known entry inhibitors. The results obtained in this thesis show that the developed compounds are unique and worthy of further examinatio

Cationic amphiphilic drugs as potential anticancer therapy for PDAC

Part of special issue: 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Barcelona, Spain 28 October 2022 10:00–15:00: POSTER SESSION: Drug Screenin

Controlling Pd-Catalyzed N-Arylation and Dimroth Rearrangement in the Synthesis of N,1-Diaryl-1H-tetrazol-5-amines

The Pd-catalyzed N-arylation method for the synthesis of eighteen N,1-diaryl-1H-tetrazol-5-amine derivatives is reported. By running the reactions at 35 °C, compounds were isolated as single isomers since the undesired Dimroth rearrangement was completely suppressed. Furthermore, the Dimroth rearrangement of N,1-diaryl-1H-tetrazol-5-amines was rationalized by conducting comprehensive experiments and NMR analysis as well as density functional theory (DFT) calculations of thermodynamic stability of the compounds. It was established that the Dimroth rearrangement is thermodynamically controlled, and the equilibrium of the reaction is determined by the stability of the corresponding isomers. The mechanism was investigated by additional DFT calculations, and the opening of the tetrazole ring was shown to be the rate-determining step. By maneuvering Pd-catalyzed N-arylation and the subsequent Dimroth rearrangement, two more N,1-diaryl-1H-tetrazol-5-amine derivatives were acquired, which otherwise cannot be synthesized by employing the C–N cross-coupling reaction.This is the peer-reviewed, authors’ version of the article: Nikolić, A., Stanić, J., Zlatar, M., Gruden, M., Anđelković, B., Selaković, Ž., Ajdačić, V.,& Opsenica, I. (2021). Controlling Pd-Catalyzed N-Arylation and Dimroth Rearrangement in the Synthesis of N,1-Diaryl-1H-tetrazol-5-amines. The Journal of Organic Chemistry, American Chemical Society (ACS)., 86(6), 4794-4803. [https://doi.org/10.1021/acs.joc.1c00282]This document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [https://doi.org/10.1021/acs.joc.1c00282]The published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4358]The supporting information: [https://cherry.chem.bg.ac.rs/handle/123456789/4360

Supporting information for the article: Nikolić, A., Stanić, J., Zlatar, M., Gruden, M., Anđelković, B., Selaković, Ž., Ajdačić, V.,& Opsenica, I. (2021). Controlling Pd-Catalyzed N-Arylation and Dimroth Rearrangement in the Synthesis of N,1-Diaryl-1H-tetrazol-5-amines. The Journal of Organic Chemistry, American Chemical Society (ACS)., 86(6), 4794-4803. https://doi.org/10.1021/acs.joc.1c00282

Copies of 1H and 13C NMR spectra for the synthesized compounds; Extended computational results, and total electronic energies, number of imaginary frequencies; Cartesian coordinates of all structures.This is the supporting information for the article: Nikolić, A., Stanić, J., Zlatar, M., Gruden, M., Anđelković, B., Selaković, Ž., Ajdačić, V.,& Opsenica, I. (2021). Controlling Pd-Catalyzed N-Arylation and Dimroth Rearrangement in the Synthesis of N,1-Diaryl-1H-tetrazol-5-amines. The Journal of Organic Chemistry, American Chemical Society (ACS)., 86(6), 4794-4803. [https://doi.org/10.1021/acs.joc.1c00282]The published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4358]The peer-reviewed version: [https://cherry.chem.bg.ac.rs/handle/123456789/4359

Supplementary data for the article: Selaković, Z.; Soloveva, V.; Gharaibeh, D. N.; Wells, J.; Šegan, S.; Panchal, R. G.; Šolaja, B. A. Anti-Ebola Activity of Diazachrysene Small Molecules. ACS Infectious Diseases 2016, 1 (6), 264–271. https://doi.org/10.1021/acsinfecdis.5b00028

Supporting information for: [https://doi.org/10.1021/acsinfecdis.5b00028]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2035

Supplementary data for the article: Selaković, Z.; Soloveva, V.; Gharaibeh, D. N.; Wells, J.; Šegan, S.; Panchal, R. G.; Šolaja, B. A. Anti-Ebola Activity of Diazachrysene Small Molecules. ACS Infectious Diseases 2016, 1 (6), 264–271. https://doi.org/10.1021/acsinfecdis.5b00028

Supporting information for: [https://doi.org/10.1021/acsinfecdis.5b00028]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2035

Dominantna svojstva efikasnog fotosintetično-fluorescentnog modela u oplemenjivanju i savremenoj proizvodnji kvalitetnog merkatilnog kukuruza

The following three prestigious maize inbred lines with erect top leaves: ZPPL 16, ZPPL 218 and ZPPL 62 were observed in this study. Each of these inbreds, either as a female or a male component, was included into the development of over 45 maize hybrids. However, maize hybrids ZP 431, ZP 434, ZP 578 and ZP 684 are widely commercially used in this medium-term period. This study conforms the hypothesis that there are elite maize inbred lines with erect top leaves and hybrids derived from them that have a dominant property of an efficient photosynthetic-fluorescence model that is successfully used in breeding and production technologies of hybrid seed and commercial maize. The presented results on the position of top leaves, increased density, dynamics of grain dry down, quality of hybrid and commercial maize and on photosynthetic and fluorescence parameters: temperature dependence on the chlorophyll delayed fluorescence intensity, Arrhenius plot for the determination of critical temperatures (phase transition temperatures) and activation energies, show that the properties of observed inbred lines and their maize hybrids are based on positive effects and the nature of structural and functional changes that occur in their thylakoid membranes and other chemical structures of grain and leaf tissues. Furthermore, other relevant breeding and seed production properties of observed prestigious maize inbred lines and hybrids derived from them were analyzed (dependence of yields on densities and quality of commercial maize on the structure of grain and physical and chemical properties).U ovom radu potvrđuje se naša hipoteza da postoje elitne samooplodne linije i sa njima stvoreni hibridi kukuruza, sa uspravnim položajem vršnih listova, koje poseduju dominantno svojstvo efikasnog fotosintetično-fluorescentnog modela što se uspešno koristi u oplemenjivanju, savremenim tehnologijama proizvodnje hibridnog semena i merkatilnog kukuruza. Izloženi rezultati o uspravnom položaju vršnih listova, povećanoj gustini, dinamici otpuštanja vode iz zrna u periodu sazrevanja, kvalitetu semena hibridnog i merkantilnog kukuruza i o fotosintetično-fluorescentnim pokazateljima: temperaturnoj zavisnosti intenziteta zakasnele fluorescencije hlorofila, Arenijusovom kriterijumu za određivanje kritičnih temperatura (temperature faznih prelaza) i energija aktivacije, pokazuju da su svojstva proučavanih linija i njihovih hibrida kukuruza zasnovana na pozitivnim efektima i prirodi strukturnih i funkcionalnih promena, koje se odigravaju u njihovim tilakoidnim membranama i drugim hemijskim strukturama tkiva zrna i lista. U radu se analiziraju i druge relevantne selekcione i semenarske karakteristike proučavanih prestižnih samooplodnih linija kukuruza i sa njima stvorenih hibrida kukuruza (zavisnost prinosa od gustine i kvalitet merkantilnog kukuruza preko strukture zrna i fizičkih i hemijskih parametara)

A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor

Ebola (EBOV) and Marburg (MARV) filoviruses are highly infectious pathogens causing deadly hemorrhagic fever in humans and non-human primates. Promising vaccine candidates providing immunity against filoviruses have been reported. However, the sporadic nature and swift progression of filovirus disease underlines the need for the development of small molecule therapeutics providing immediate antiviral effects. Herein we describe a brief structural exploration of two previously reported diazachrysene (DAAC)-based EBOV inhibitors. Specifically, three analogs were prepared to examine how slight substituent modifications would affect inhibitory efficacy and inhibitor-mediated toxicity during not only EBOV, but also MARV cellular infection. Of the three analogs, one was highly efficacious, providing IC50 values of 0.696 mu M +/- 0.13 mu M and 2.76 mu M +/- 0.21 mu M against EBOV and MARV infection, respectively, with little or no associated cellular toxicity. Overall, the structure-activity and structure-toxicity results from this study provide a framework for the future development of DAAC-based filovirus inhibitors that will be both active and non-toxic in vivo

Supplementary data for article: Selaković, Ž.; Tran, J. P.; Kota, K. P.; Lazić, M.; Retterer, C.; Besh, R.; Panchal, R. G.; Soloveva, V.; Sean, V. A.; Jay, W. B.; et al. Second Generation of Diazachrysenes: Protection of Ebola Virus Infected Mice and Mechanism of Action. European Journal of Medicinal Chemistry 2019, 162, 32–50. https://doi.org/10.1016/j.ejmech.2018.10.061

Supplementary material for: [https://www.sciencedirect.com/science/article/pii/S0223523418309383?via%3Dihub]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/360]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/2966