2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

Abstract

In the continuing search for novel, biologically effective heterocyclic agents, several methods for the synthesis of 2‐heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones have been developed: thiolation of oxo derivatives, [5+1] cyclocondensation of [2‐(3‐heteroaryl‐[1,2,4]triazol‐5‐yl)phenyl]amines with carbon disulfide, potassium ethyl xanthogenate, or aryl isothiocyanates, and in situ reaction of 2‐isothiocyanatobenzonitrile with hydrazides. A series of N‐R‐2‐[(2‐heteroaryl‐[1,2,4]triazole‐[1,5‐c]quinazoline‐5‐yl)thio]acetamides were obtained by aminolysis of the corresponding acetic acids and alkylation of potassium thiolates with N‐R‐2‐chloroacetamides. It was established that some potassium thiolates, 4 a–4 d, 4 h, and 4 i, had high antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration of 12.5 μg mL−1 and minimum bactericidal concentration of 25 μg mL−1, which exceeded the values for trimethoprim. In addition, {2‐[3‐(1 H‐indole‐2‐yl)‐1 H‐1,2,4‐triazol‐5‐yl]phenyl}amine 2 i was investigated in the concentration range 100–0.01 μM at 59 lines of nine cancer cell types, and showed a mean effective concentration at 3.12–7.03 μM and cytotoxic effect at 15.56–67.38 μM. The possible mechanisms of activity were predicted by molecular docking studies to S. aureus dihydrofolate reductase and epidermal growth factor receptor kinase.

Synthesis and Characterization of Novel N‐(Phenyl, Benzyl, Hetaryl)‐2‐([1,2,4]Triazolo[1,5‐c]Quinazolin‐2‐ylthio)Acetamides by Spectral Data, Antimicrobial Activity, Molecular Docking and QSAR Studies

“…Flexible molecular docking was carried out using the software package OpenEye by the reported earlier procedure .…”

“…aeruginosa ATCC 27853, E . coli ATCC 25922, Klebsiella pneumonia 68) according to the earlier reported procedure .…”

“…According to the latest paper of Spellberg and Shlaes about antibiotic resistance among the top areas of unmet medical treatment are extreme drug‐resistant (XDR) and pan drug‐resistant (PDR) Gram negative bacilli infection, common community‐onset infections such as urinary tract infections and intra‐abdominal infections caused by gram negative bacilli to all oral options, XDR/PDR tuberculosis, bloodstream, and bone infections caused by MRSA, and XDR/PDR gonorrhea. Thus, it is of undoubted interest, to synthesize and investigate for antimicrobial activity the novel antimicrobial agents as continuation of novel derivatives of [1,2,4]triazolo[1,5‐ c ]quinazoline search, which were already proven to have high antifungal activity against Candida ablicans , namely ([1,2,4]triazolo[1,5‐ c ]quinazolin‐2‐ylthio)acetic and propionic acids, A , and antimicrobial activity against Staphylococcus aureus – potassium 2‐heteroaryl‐[1,2,4]triazolo[1,5‐ c ]quinazoline‐5‐thiolates, B (Fig. ).…”

2-(Azolyl)anilines: methods of synthesis, cyclocondensations, and biological properties

“…55,65 It was shown, that compounds 62 possess a modest activity, having MIC and MBC values toward the strains of E. coli and S. aureus in the range of 50-100 and 100-200 mg/ml, respectively. However, the derivatives with 2(3)-thienyl substituents at position 5 of the azole ring were active against S. aureus with MIC of 25 mg/ml.…”

“…55,57,58 The high levels of growth inhibition served as a cytotoxicity marker of potential possession of the antitumor activity. It was shown, that tetrazolyl-and ([1,2,4]-triazol-3-yl)anilines their condensed derivatives (compounds 62, 137-139, 142-144) possess antitumor activity against 60 human cancer cell lines.…”