Synthesis, characterization, X-ray diffraction, in silico studies and in vitro biological evaluation of acylthiourea-derived thiazole-2-imines.
5 affiliations
- 1Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand Private Bag X3 Johannesburg 2050 South Africa [email protected].
- 2Discipline of Chemistry, School of Agriculture and Engineering, University of KwaZulu-Natal Private Bag X54001, Westville Durban 4000 South Africa [email protected].
- 3HIV Pathogenesis Programme, Doris Duke Medical Research Institute, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal Durban 4001 South Africa.
- 4School of Laboratory Medicine and Medical Science, College of Health Sciences, University of KwaZulu-Natal Medical School Campus Durban 4001 South Africa.
- 5Department of Chemical and Physical Sciences, Walter Sisulu University (WSU) Private Bag X01 Mthatha Eastern Cape 4099 South Africa.
Abstract
A series of thiazole-2-imines (1a-1f) with unsubstituted aryl groups or aryl groups bearing methyl, methoxy, fluoro, or nitro substituents was designed using selected structural features of thiamine as inspiration. The compounds were synthesized from monosubstituted acylthioureas and para-substituted phenacyl bromides in 82-95% yields. Various spectroscopic techniques and high-resolution mass spectrometric analysis confirmed product formation. Single-crystal X-ray diffraction of the methyl/methyl, fluoro/fluoro, and nitro/fluoro-substituted derivatives established the Z-configured scaffold. Density functional theory (DFT) calculations supported the observed experimental geometries. Flexophore analysis indicated low-to-moderate similarity to thiamine, with the nitro/fluoro-substituted derivative yielding the highest score (41%). Docking of hypothetical pyrophosphorylated derivatives and the parent thiazole-2-imines suggested that these compounds could be accommodated within selected binding pockets of thiamine-dependent enzymes and TB- or HIV-related proteins. However, these predictions do not establish antimetabolite activity or specific molecular targets. In silico absorption, distribution, metabolism, excretion, and toxicity profiling predicted no Lipinski violations, low metabolic liability, and at least 74% oral absorption. In vitro evaluation against Mycobacterium tuberculosis H37Rv showed modest antimycobacterial activity, with MIC₉₀ values ranging from 125 to 250 µM. The nitro/fluoro substituted derivative (1f) showed the strongest anti-HIV activity (IC₅₀ = 75.86 µM) and the most favourable HIV-specific selectivity index, followed by the methyl/methyl-substituted derivative (1b).
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BibTeX
@article{kangara2026synthesis,
title = {{Synthesis, characterization, X-ray diffraction, in silico studies and in vitro biological evaluation of acylthiourea-derived thiazole-2-imines.}},
author = {Edmore F Kangara and Thishana Singh and Phindile Khoza and Darian Naidu and Nompumelelo P Mkwananzi and Sibusiso Senzani and Oluwatoba E Oyeneyin and Manuel A Fernandes and Werner Van Zyl and Matshawandile Tukulula},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra07024h},
url = {https://europepmc.org/article/MED/42851996},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synthesis, characterization, X-ray diffraction, in silico studies and in vitro biological evaluation of acylthiourea-derived thiazole-2-imines.
AU - Edmore F Kangara
AU - Thishana Singh
AU - Phindile Khoza
AU - Darian Naidu
AU - Nompumelelo P Mkwananzi
AU - Sibusiso Senzani
AU - Oluwatoba E Oyeneyin
AU - Manuel A Fernandes
AU - Werner Van Zyl
AU - Matshawandile Tukulula
PY - 2026
DA - 2026/10/08
JO - RSC advances
DO - 10.1039/d6ra07024h
UR - https://europepmc.org/article/MED/42851996
AB - A series of thiazole-2-imines (1a-1f) with unsubstituted aryl groups or aryl groups bearing methyl, methoxy, fluoro, or nitro substituents was designed using selected structural features of thiamine as inspiration. The compounds were synthesized from monosubstituted acylthioureas and para-substituted phenacyl bromides in 82-95% yields. Various spectroscopic techniques and high-resolution mass spectrometric analysis confirmed product formation. Single-crystal X-ray diffraction of the methyl/methyl, fluoro/fluoro, and nitro/fluoro-substituted derivatives established the Z-configured scaffold. Density functional theory (DFT) calculations supported the observed experimental geometries. Flexophore analysis indicated low-to-moderate similarity to thiamine, with the nitro/fluoro-substituted derivative yielding the highest score (41%). Docking of hypothetical pyrophosphorylated derivatives and the parent thiazole-2-imines suggested that these compounds could be accommodated within selected binding pockets of thiamine-dependent enzymes and TB- or HIV-related proteins. However, these predictions do not establish antimetabolite activity or specific molecular targets. In silico absorption, distribution, metabolism, excretion, and toxicity profiling predicted no Lipinski violations, low metabolic liability, and at least 74% oral absorption. In vitro evaluation against Mycobacterium tuberculosis H37Rv showed modest antimycobacterial activity, with MIC₉₀ values ranging from 125 to 250 µM. The nitro/fluoro substituted derivative (1f) showed the strongest anti-HIV activity (IC₅₀ = 75.86 µM) and the most favourable HIV-specific selectivity index, followed by the methyl/methyl-substituted derivative (1b).
SN - 2046-2069
ER -