ADMET and DMPK, Vol. 14 , 2026.
Original scientific paper
https://doi.org/10.5599/admet.3139
Anti-infective macrozones: design, biological evaluation and structure-activity relationships
Tomislav Jednačak
orcid.org/0000-0003-1620-094X
; University of Zagreb, Faculty of Science, Department of Chemistry
Višnja Stepanić
orcid.org/0000-0001-9518-4153
; Division of Electronics, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia
Iva Habinovec
orcid.org/0009-0009-9925-9293
; Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
Ivana Mikulandra
; Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
Kristina Smokrović
orcid.org/0000-0002-9077-5293
; Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
Hana Čipčić Paljetak
; Center for Translational and Clinical Research, School of Medicine, University of Zagreb, Šalata 3, HR-10000 Zagreb, Croatia
Mirjana Bukvić
; Selvita, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia
Jelena Parlov Vuković
; NMR Centre, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia
Ivan Grgičević
orcid.org/0009-0009-5708-6363
; Labtim Adria d.o.o., Jaruščica 7A, HR-10020 Zagreb, Croatia
Leda Divjak
; Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
Klaus Zangger
orcid.org/0000-0003-1682-1594
; Organic and Bioorganic Chemistry, Institute of Chemistry, University of Graz, Heinrichstraße 28 A-8010 Graz, Austria
Predrag Novak
; Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
*
* Corresponding author.
Abstract
Background and purpose: To discover novel compounds active against sensitive and resistant bacterial strains, a series of novel azithromycin-thiosemicarbazone conjugates, the macrozones, have been synthesized and their biological activity evaluated with corresponding (quantitative) structure-activity relationship ((Q)SAR) analyses conducted. Experimental approach: A systematic variation of thiosemicarbazone side-chains and coupling at positions 4''-, 3-, and 9a of the azithromycin scaffold has resulted in a novel class of bacterial ribosome inhibitors. Key results: Compared to azithromycin, the activity of 4''-macrozones has shown the greatest improvements against efflux-resistant S. pneumoniae and S. aureus, as well as very good activity of 4'' derivatives against E. faecalis. QSAR calculations indicate that the antibacterial activity of macrozones is primarily determined by the position of the thiosemicarbazone side chain. Among the conjugated derivatives, the 4''-substituted macrozones exhibit the highest overall activity against a range of sensitive and efflux-resistant Gram-positive bacteria, as well as against Gram-negative E. coli strains, while those substituted at 9a- and 3- positions are found to be less potent. The antibacterial activity of macrozones is favourably influenced by larger fractions of their cationic and zwitterionic forms, their capacity for hydrogen bond formation, and the extension of p-electron delocalization involving the thiosemicarbazone moiety. Conclusion: The results obtained provide a sound basis for guiding further medicinal chemistry efforts toward the discovery of more potent macrolide anti-infectives, with particular emphasis on resistant bacteria that pose a serious threat to human health.
Keywords
Azithromycin conjugates; thiosemicarbazones; synthesis; biological activity; resistance
Hrčak ID:
345187
URI
Publication date:
14.1.2026.
Visits: 167 *