Synthesis of significant nitroimidazole-triazole-pyridine hybrids and their molecular modeling as antimicrobial agents

A series of nitroimidazole-triazole hybrids
7a-d
and
10a-d
have been synthesized through the Huisgen cycloaddition of 1-(2-azidoacetyl)-2-methyl-5-nitro-1
H
-imidazole
(3)
with 2-((4-propargyloxy)benzylidene)malononitrile
(4)
or ethyl 2-cyano-3-((4-propargyloxy)phenyl) acrylate
(8)
, followed by cyclization of imidazole-triazole compounds
(5 and 9)
with
N
-aryl cyanoacetamides
6a-d
. The DFT calculations for the synthesized nitroimidazole-based hybrids revealed comparable twisted configurations and similar Highest occupied molecular orbitals (HOMO)-lowest unoccupied molecular orbital (LUMO) constructions. Consequently, their energy gap ranged from 2.93 to 3.33 eV, where analogues
7b
and
5
exhibited the utmost and least values, respectively. In addition, the antimicrobial effectiveness of the prepared nitroimidazole-based hybrids against Gram(+ve), Gram(-ve), and fungal strains were assessed using MIC and IZ assays. Imidazole-triazole hybrids
7a
, 
7b
, and 
10d
 displayed the highest activity, particularly against
S. aureus
,
B. subtilis
, and
E. coli
(minimum inhibitory concentrations (MIC) = 3.125-6.25 µg.mL
-1
), comparable to the reference antibiotics. However, nitroimidazole-triazole hybrid
9
demonstrated a robust fungicidal effect on
C. albicans
(MIC = 3.125 µg.mL
-1
), comparable to cycloheximide. The molecular docking study was performed to evaluate interactions of the manufactured series with the target protein (PDB: 1BDD). The hybrids
5
and 
10d
 presented the maximum binding affinities (S = -7.1215 and -7.2123 kcal.mol
-1
). These findings suggest that nitroimidazole-hybrids, particularly 
10d
 and 
5
, represented promising scaffolds for further development due to their strong binding affinities and diverse interaction profiles. Furthermore, the Swiss Absorption, distribution, metabolism, and excretion (ADME) study provided an in-depth pharmacokinetic evaluation of the new nitroimidazole hybrids, a robust tool for predicting drug-likeness and bioavailability. Hybrids
5
 and 
9
 exhibited favorable solubility with low molecular weights, while hybrids
7a-d
 and 
10a-d
 showed moderate solubility but higher molecular weights and increased Lipinski violations. The bioavailability scores showed moderate to low, with nitroimidazole-hybrids
5
 and 
9
. These pharmacokinetic results offered valuable insights into the drug-likeness and potential therapeutic pertinency of these hybrids.