The antitumor drug 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ (1)) along with a number of newly synthesized tirapazamine derivatives (TPZs) bearing substitutions at the 3-amine position of TPZ (1) were estimated for their antibacterial activity against representative Gram-negative Escherichia coli (ATCC 25922) and Salmonella enterica (SL 5676), as well as Gram-positive Staphylococcus aureus (ATCC 25923) bacterial strains. Their activities in terms of minimum inhibitory concentrations (MICs) varied in the range of 1.1 µM (0.25 µg/mL)–413 µM (128 µg/mL). Amongst the most potent derivatives (1–6), acetyl- and methoxycarbonyl-substituted TPZs (2 and 4) were the strongest agents, which exhibited approximately 4–30 fold greater activities compared to those of TPZ (1) along with the reference drugs chloramphenicol (CAM) and nitrofurantoin (NFT). The inhibitory activities of the compounds were highly impacted by their structural features. No reliable relationships were established between activities and the electron-accepting potencies of the whole set of studied compounds, while the activities of TPZ drug (1) and the structurally uniform set of molecules (2–6) were found to increase with an increase in their electron-accepting potencies obtained by means of density functional theory (DFT) computation. A greater steric, lipophilic and polar nature of the substituents led to a lower activity of the compounds. The combined antibacterial in vitro trial gave clear evidence that TPZs coupled with the commonly utilized antibiotics ciprofloxacin (Cipro) and nitrofurantoin (NFT) could generate enhanced (suggestive of partial and virtually complete synergistic) and additive effects. The strongest effects were defined for TPZs–NFT combinations, which resulted in a notable reduction in the MICs of di-N-oxides. These preliminary findings suggest that the synthesized novel di-N-oxides might be used as sole agents or applied as antibiotic complements.

Triazole derivatives constitute an important group of heterocyclic compounds have have been the subject of extensive study in the recent past. These compounds have shown a wide range of biological and pharmacological activities. In this work, new fused tricyclic 1-(3-nitrophenyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]-benzodiazepines have been synthesized by the thermal cyclization of N'-(2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-3-nitrobenzohydrazides. After screening ethanol, toluene and 1-butanol as solvents, butanol-1 was found to be the best choice for the cyclization reaction in order to obtain the highest yields of tricyclic derivatives. The chemical structures of the synthesized compounds were elucidated by the analysis of their IR, ¹H- and ¹³C-NMR spectral data. For tentative rationalization of the reaction processes, the global and local reactivity indices of certain compounds, taking part in the reaction pathway, were assessed by means of quantum mechanical calculations using the conceptual density functional theory (DFT) approach. This work could be useful for the synthesis of new heterocyclic compounds bearing a fused triazole ring.