Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents

Muhammad Sajid; Hina Siddiqui; Humaira Zafar; Sammer Yousuf; Michael D. Threadgill; Muhammad Iqbal Choudhary

doi:10.1080/17568919.2024.2359362

Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents

Muhammad Sajid
, Hina Siddiqui^*
, Humaira Zafar
, Sammer Yousuf
, Michael D. Threadgill
, Muhammad Iqbal Choudhary

^*Corresponding author for this work

Department of Life Sciences

University of Karachi
Universitas Sumatera Utara
University of Bath
King Abdulaziz University
Airlangga University

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Pages (from-to)	1485-1497
Number of pages	13
Journal	Future Medicinal Chemistry
Volume	16
Issue number	15
Early online date	02 Jul 2024
DOIs	https://doi.org/10.1080/17568919.2024.2359362
Publication status	Published - 02 Aug 2024

Keywords

(±)-Aminoglutethimide
cutaneous leishmaniasis
cytotoxicity
thiourea
Parasitic Sensitivity Tests
Antiprotozoal Agents/pharmacology
Humans
Thiourea/pharmacology
Structure-Activity Relationship
Leishmania tropica/drug effects
Animals
Molecular Docking Simulation
Molecular Structure
Leishmania major/drug effects

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10.1080/17568919.2024.2359362

Accepted manuscriptAccepted author manuscript, 737 KBLicence: CC BY-NC
Supplementary MaterialsData, 17 MBLicence: CC BY

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title = "Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents",

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, Parasitic Sensitivity Tests, Antiprotozoal Agents/pharmacology, Humans, Thiourea/pharmacology, Structure-Activity Relationship, Leishmania tropica/drug effects, Animals, Molecular Docking Simulation, Molecular Structure, Leishmania major/drug effects",

author = "Muhammad Sajid and Hina Siddiqui and Humaira Zafar and Sammer Yousuf and Threadgill, \{Michael D.\} and Choudhary, \{Muhammad Iqbal\}",

note = "Publisher Copyright: {\textcopyright} 2024 Informa UK Limited, trading as Taylor \& Francis Group.",

year = "2024",

month = aug,

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doi = "10.1080/17568919.2024.2359362",

language = "English",

volume = "16",

pages = "1485--1497",

journal = "Future Medicinal Chemistry",

issn = "1756-8919",

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number = "15",

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TY - JOUR

T1 - Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents

AU - Sajid, Muhammad

AU - Siddiqui, Hina

AU - Zafar, Humaira

AU - Yousuf, Sammer

AU - Threadgill, Michael D.

AU - Choudhary, Muhammad Iqbal

PY - 2024/8/2

Y1 - 2024/8/2

N2 - 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.

AB - 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.

KW - (±)-Aminoglutethimide

KW - cutaneous leishmaniasis

KW - cytotoxicity

KW - thiourea

KW - Parasitic Sensitivity Tests

KW - Antiprotozoal Agents/pharmacology

KW - Humans

KW - Thiourea/pharmacology

KW - Structure-Activity Relationship

KW - Leishmania tropica/drug effects

KW - Animals

KW - Molecular Docking Simulation

KW - Molecular Structure

KW - Leishmania major/drug effects

UR - https://www.scopus.com/pages/publications/85197311235

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DO - 10.1080/17568919.2024.2359362

M3 - Article

C2 - 38953461

AN - SCOPUS:85197311235

SN - 1756-8919

VL - 16

SP - 1485

EP - 1497

JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

IS - 15

ER -

Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents

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