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. 2024 Aug 2;16(15):1485-1497.
doi: 10.1080/17568919.2024.2359362. Epub 2024 Jul 2.

Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents

Muhammad Sajid  1 , Hina Siddiqui  1   2 , Humaira Zafar  3 , Sammer Yousuf  1 , Michael D Threadgill  4   5 , Muhammad Iqbal Choudhary  1   3   6   7
Affiliations

Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents

Muhammad Sajid et al. Future Med Chem. .

Abstract

Aim: We aim to develop new anti-leishmanial agents against Leishmania major and Leishmania tropica.Materials & methods: A total of 23 thiourea derivatives of (±)-aminoglutethimide were synthesized and evaluated for in vitro activity against promastigotes of L. major and L. tropica.Results & conclusion: The N-benzoyl analogue 7p was found potent (IC50 = 12.7 μM) against L. major and non toxic to normal cells. The docking studies, indicates that these inhibitors may target folate and glycolytic pathways of the parasite. The N-hexyl compound 7v was found strongly active against both species, and lacked cytotoxicity against normal cells, whereas compound 7r, with a 3,5-bis-(tri-fluoro-methyl)phenyl unit, was active against Leishmania, but was cytotoxic in nature. Compound 7v was thus identified as a hit for further studies.

Keywords: (±)-Aminoglutethimide; cutaneous leishmaniasis; cytotoxicity; thiourea.

Plain language summary

[Box: see text].

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Conflict of interest statement

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Compounds with good anti-leishmanial activity.
Figure 2.
Figure 2.
Synthesis of thiourea derivatives of (±)aminoglutethimide.
Figure 3.
Figure 3.
Docking scores of active compounds against (A) pteridine reductase (PTR1) from Leishmania major, (B) pyruvate Kinase (PK) and (C) glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Leishmania Mexicana.
Figure 4.
Figure 4.
Predictive binding energies of active compounds against (A) pteridine Reductase (PTR1) from Leishmania major, (B) pyruvate Kinase (PK) and (C) glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Leishmania Mexicana.
See this image and copyright information in PMC

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