3H-1,5-Benzodiazepine Derivatives as Novel Antimalarial Agents: Synthesis, Biological Evaluation and Computational Target Exploration
8 affiliations
- 1Medicinal Chemistry Research Laboratory
- 2Birla Institute of Technology and Science
- 3Department of Biomedical, Surgical and Dental Sciences, University of Milan, Pascal Street 36, Milan, Italy, 20133
- 4Cancer Pharmacology Division
- 5CSIR-Indian Institute of Integrative Medicine
- 6Academy of Scientific and Innovative Research (AcSIR
- 7Department of Chemistry
- 8Birla Institute of Technology and Science Pilani, Hyderabad Campus
Abstract
Malaria remains a major global health challenge worldwide and the emergence of resistance to frontline antimalarial drugs, including artemisinin-based combination therapies, underscores the need for novel antimalarial agents with distinct mechanism of action. Herein, eighteen novel 3H-1,5-benzodiazepine derivatives (5a-r) were synthesized and evaluated against chloroquine-sensitive (PfD10) and chloroquine resistant (PfW2) strains of Plasmodium falciparum. Cytotoxicity was assessed against human hepatocellular carcinoma (HepG2) cells to determine preliminary selectivity. Compound 5e, 5k, 5m, 5n, and 5o exhibited promising anti-plasmodial activity. Compound 5o was the most potent, with IC50 values of 5.88 ± 0.36 and 6.68 ± 2.03 µM against PfD10 and PfW2, respectively, whereas 5k and 5n displayed the most favourable selectivity profiles. Considering the potency of compounds 5k and 5o, we further evaluated them against human G9a, a histone lysine methyltransferase which showed exhibited weak inhibition relative to the reference inhibitor BIX-01294. Computational studies that include frontier molecular orbital analysis, molecular docking, MM-GBSA calculations, molecular dynamics simulations and post-simulation analyses were performed to support their binding modes and stability within the active sites of parasite-specific PfSET3 and human G9a. Thus, this study identifies 3H-1,5-benzodiazepine scaffold as a promising and underexplored starting point for new antimalarial agents, with PfSET3 emerging as an interesting target worth further investigation.
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BibTeX
@misc{kuthe20263h15benzodiazepine,
title = {{3H-1,5-Benzodiazepine Derivatives as Novel Antimalarial Agents: Synthesis, Biological Evaluation and Computational Target Exploration}},
author = {Pranali Vijaykumar Kuthe and Mohammed Muzaffar-Ur-Rehman and Abirla Murugan and Mina Rashid and Nicoletta Basilico and Sajad Hussain Syed and Kondapalli Venkata Gowri Chandra Sekhar and Sankaranarayanan Murugesan and Murugesan Sankaran},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010605/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010605/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - 3H-1,5-Benzodiazepine Derivatives as Novel Antimalarial Agents: Synthesis, Biological Evaluation and Computational Target Exploration
AU - Pranali Vijaykumar Kuthe
AU - Mohammed Muzaffar-Ur-Rehman
AU - Abirla Murugan
AU - Mina Rashid
AU - Nicoletta Basilico
AU - Sajad Hussain Syed
AU - Kondapalli Venkata Gowri Chandra Sekhar
AU - Sankaranarayanan Murugesan
AU - Murugesan Sankaran
PY - 2026
DA - 2026/10/16
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010605/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010605/v1
AB - Malaria remains a major global health challenge worldwide and the emergence of resistance to frontline antimalarial drugs, including artemisinin-based combination therapies, underscores the need for novel antimalarial agents with distinct mechanism of action. Herein, eighteen novel 3H-1,5-benzodiazepine derivatives (5a-r) were synthesized and evaluated against chloroquine-sensitive (PfD10) and chloroquine resistant (PfW2) strains of Plasmodium falciparum. Cytotoxicity was assessed against human hepatocellular carcinoma (HepG2) cells to determine preliminary selectivity. Compound 5e, 5k, 5m, 5n, and 5o exhibited promising anti-plasmodial activity. Compound 5o was the most potent, with IC50 values of 5.88 ± 0.36 and 6.68 ± 2.03 µM against PfD10 and PfW2, respectively, whereas 5k and 5n displayed the most favourable selectivity profiles. Considering the potency of compounds 5k and 5o, we further evaluated them against human G9a, a histone lysine methyltransferase which showed exhibited weak inhibition relative to the reference inhibitor BIX-01294. Computational studies that include frontier molecular orbital analysis, molecular docking, MM-GBSA calculations, molecular dynamics simulations and post-simulation analyses were performed to support their binding modes and stability within the active sites of parasite-specific PfSET3 and human G9a. Thus, this study identifies 3H-1,5-benzodiazepine scaffold as a promising and underexplored starting point for new antimalarial agents, with PfSET3 emerging as an interesting target worth further investigation.
ER -