Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation.

Ibrahim, TM; Abada, G; Dammann, M; Maklad, RM; Eldehna, WM; Salem, R; Abdelaziz, MM; El-Domany, RA; Bekhit, AA; Beockler, FM

Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation.

Ibrahim, TM Abada, G Dammann, M Maklad, RM Eldehna, WM Salem, R Abdelaziz, MM El-Domany, RA Bekhit, AA Beockler, FM

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Publisher:: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Publication Type:: Journal Article
Citation:: Eur J Med Chem, 2023, 257, pp. 115534
Issue Date:: 2023-09-05

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Field	Value	Language
dc.contributor.author	Ibrahim, TM
dc.contributor.author	Abada, G
dc.contributor.author	Dammann, M
dc.contributor.author	Maklad, RM
dc.contributor.author	Eldehna, WM
dc.contributor.author	Salem, R
dc.contributor.author	Abdelaziz, MM
dc.contributor.author	El-Domany, RA
dc.contributor.author	Bekhit, AA
dc.contributor.author	Beockler, FM
dc.date.accessioned	2025-01-31T01:12:33Z
dc.date.available	2023-05-28
dc.date.available	2025-01-31T01:12:33Z
dc.date.issued	2023-09-05
dc.identifier.citation	Eur J Med Chem, 2023, 257, pp. 115534
dc.identifier.issn	0223-5234
dc.identifier.issn	1768-3254
dc.identifier.uri	http://hdl.handle.net/10453/184732
dc.description.abstract	Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198-0.096 μM, compared to IC50 value of 0.19420 μM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 μM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
dc.relation.ispartof	Eur J Med Chem
dc.relation.isbasedon	10.1016/j.ejmech.2023.115534
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Medicinal & Biomolecular Chemistry
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.classification	3405 Organic chemistry
dc.subject.mesh	Animals
dc.subject.mesh	Antimalarials
dc.subject.mesh	Antiprotozoal Agents
dc.subject.mesh	Antitubercular Agents
dc.subject.mesh	Chloroquine
dc.subject.mesh	Folic Acid Antagonists
dc.subject.mesh	Hydroxyquinolines
dc.subject.mesh	Leishmania major
dc.subject.mesh	Mammals
dc.subject.mesh	Molecular Docking Simulation
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Quinolines
dc.subject.mesh	Animals
dc.subject.mesh	Mammals
dc.subject.mesh	Leishmania major
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Quinolines
dc.subject.mesh	Chloroquine
dc.subject.mesh	Hydroxyquinolines
dc.subject.mesh	Folic Acid Antagonists
dc.subject.mesh	Antitubercular Agents
dc.subject.mesh	Antiprotozoal Agents
dc.subject.mesh	Antimalarials
dc.subject.mesh	Molecular Docking Simulation
dc.subject.mesh	Animals
dc.subject.mesh	Antimalarials
dc.subject.mesh	Antiprotozoal Agents
dc.subject.mesh	Antitubercular Agents
dc.subject.mesh	Chloroquine
dc.subject.mesh	Folic Acid Antagonists
dc.subject.mesh	Hydroxyquinolines
dc.subject.mesh	Leishmania major
dc.subject.mesh	Mammals
dc.subject.mesh	Molecular Docking Simulation
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Quinolines
dc.title	Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation.
dc.type	Journal Article
utslib.citation.volume	257
utslib.location.activity	France
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access	*
dc.date.updated	2025-01-31T01:12:25Z
pubs.publication-status	Published
pubs.volume	257

Abstract:

Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198-0.096 μM, compared to IC50 value of 0.19420 μM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 μM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.

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