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Volume 31
Issue 1
10.3390/molecules31010125
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Newly Synthesized Telmisartan–Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells

by
Dragana Vukadinović
1,2,
Ana Damjanović
3,
Miodrag Vuković
3,
Olivera Čudina
1,
Jelena Grahovac
3,* and
Vladimir Dobričić
1,*
1
Department of Pharmaceutical Chemistry, University of Belgrade—Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
2
Department for Pharmacy, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia
3
Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
*
Authors to whom correspondence should be addressed.
Molecules 2026, 31(1), 125; https://doi.org/10.3390/molecules31010125 (registering DOI)
Submission received: 20 November 2025 / Revised: 14 December 2025 / Accepted: 26 December 2025 / Published: 29 December 2025
(This article belongs to the Special Issue Novel Heterocyclic Compounds: Synthesis and Applications)
Versions Notes

Abstract

Telmisartan, an angiotensin II type 1 receptor (AT1R) antagonist, possesses cytotoxic activity towards BRAF-mutated melanoma cell lines. However, its antihypertensive effects limit its use in the population of normotensive patients. To mitigate this shortcoming, a group of eight telmisartan–amino acid conjugates, designed to have reduced or no AT1R affinity with enhanced cellular uptake, were synthesized by the coupling reaction in yields ranging from 34% to 60%. Their cytotoxicity was tested on BRAF V600E-mutated melanoma cell lines (A375 and 518A2), and compounds 1, 3, and 8 stood out as the best candidates. These three compounds were also tested on the vemurafenib-resistant (A375R) and normal (HaCaT and MRC-5) cell lines, and compound 8 showed better cytotoxicity (IC50 = 8.84 ± 1.24 µM) and selectivity (>3.50) when compared to telmisartan (IC50 = 29.23 ± 3.88, selectivity > 2.40). The cellular uptake of compounds 1 and 8 was significantly higher than telmisartan, with substantial accumulation in the membrane and nuclear compartments. Unlike telmisartan, compounds 1, 3, and 8 did not inhibit angiotensin II-induced Ca2+ signaling, which indicates diminished AT1R binding. All three compounds induced cell cycle arrest and disrupted mitochondrial morphology and membrane potential. These findings highlight their potential as non-antihypertensive telmisartan derivatives for melanoma therapy.
Keywords: telmisartan–amino acid conjugates; anticancer effects; synthesis; melanoma telmisartan–amino acid conjugates; anticancer effects; synthesis; melanoma

Share and Cite

MDPI and ACS Style

Vukadinović, D.; Damjanović, A.; Vuković, M.; Čudina, O.; Grahovac, J.; Dobričić, V. Newly Synthesized Telmisartan–Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells. Molecules 2026, 31, 125. https://doi.org/10.3390/molecules31010125

AMA Style

Vukadinović D, Damjanović A, Vuković M, Čudina O, Grahovac J, Dobričić V. Newly Synthesized Telmisartan–Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells. Molecules. 2026; 31(1):125. https://doi.org/10.3390/molecules31010125

Chicago/Turabian Style

Vukadinović, Dragana, Ana Damjanović, Miodrag Vuković, Olivera Čudina, Jelena Grahovac, and Vladimir Dobričić. 2026. "Newly Synthesized Telmisartan–Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells" Molecules 31, no. 1: 125. https://doi.org/10.3390/molecules31010125

APA Style

Vukadinović, D., Damjanović, A., Vuković, M., Čudina, O., Grahovac, J., & Dobričić, V. (2026). Newly Synthesized Telmisartan–Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells. Molecules, 31(1), 125. https://doi.org/10.3390/molecules31010125

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