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Synthesis, antileishmanial activity and molecular modeling of new 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives

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Abstract

Due to the lack of effective vaccine(s) against leishmania and also pharmacokinetics issues of current drugs, it is necessary to discover new antileishmanial agents. Within this particular study, a series of novel 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives were synthesized (yields 69–84%) and evaluated as antileishmanial compounds (1–11). Synthetic derivatives were subjected to in vitro antileishmanial assessment against Leishmania major promastigotes by colorimetric MTT assay. Compounds 3 (IC50 38.54 µg/mL), 5 (IC50 84.75 µg/mL) and 10 (IC50 70.31 µg/mL) exhibited higher activities after 48 h but were less potent than amphotericin B (IC50 0.19 µg/mL). Antileishmanial activities indicated priority of 5-methyl-4-phenyl thiazole over furyl methyl substituents and 4-phenyl thiazole on thiourea nitrogen. N-myristoyltransferase (NMT) was selected as a validated L. major target for molecular docking studies. In silico results indicated the contribution of hydrophobic, π-stacking and H-bond interactions in binding to target. Most of the synthesized derivatives had lower binding affinities to human NMT (hNMT) than leishmanial enzyme. Docking conformations of top-ranked selective binders (compounds 3 and 5) were subjected to 50 ns MD simulations inside L. major HMT (LmNMT) active site. MD trajectories were used to extract RMSD, RMSF, Rg and durability of intramolecular/intermolecular H-bonds of the complex. It was observed that compound 3 escaped from LmNMT binding site during simulation period and no stable complex could be envisaged. Unlike 3, compound 5 attained stable binding conformation with converged stability parameters. Although mechanistic details for antileishmanial effects of synthesized derivatives are to be explored, current results may be implicated in further structure-guided approach toward potent antileishmanial agents.

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Funding

The research leading to offered results received funding from Ardabil University of Medical Sciences (ARUMS) under Grant Number IR.ARUMS.REC.1398.595.

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Authors and Affiliations

  1. Department of Microbiology and Parasitology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

    Behnam Mohammadi-Ghalehbin

  2. Research Center for Zoonoses, Parasitic and Microbial Diseases, Ardabil University of Medical Sciences, Ardabil, Iran

    Behnam Mohammadi-Ghalehbin

  3. Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, 5618953141, Ardabil, Iran

    Jafar Abbasi Shiran & Nima Razzaghi-Asl

  4. Students Research Committee, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Nastaran Gholizadeh

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  1. Behnam Mohammadi-Ghalehbin
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All authors contributed equally in this work (concept, design, definition of intellectual content, literature search, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing and manuscript review).

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Correspondence to Nima Razzaghi-Asl.

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Mohammadi-Ghalehbin, B., Shiran, J.A., Gholizadeh, N. et al. Synthesis, antileishmanial activity and molecular modeling of new 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives. Mol Divers 27, 1531–1545 (2023). https://doi.org/10.1007/s11030-022-10508-3

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