Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7 H-pyrimido[4,5- b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents

Abstract

This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI₅₀ values between 0.01 and 100 μM and LC₅₀ values in the range of 4.09 μM to >100 μM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 μg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.

Keywords: 1,3,5-triazines; antibacterial activity; anticancer activity; antifungal activity; chalcones; cytotoxicity; diazepines.

Figure 1

1,3,5-Triazine hybrids with biological properties.

Scheme 1

Synthesis of triazine-based sulfonamides 17,18.

Scheme 2

Synthesis of triazinyloxy-chalcones (20,21)a–g and triazinylamino-chalcones (23,24)a–g.

Scheme 3

Synthesis of the target triazinyloxy- and triazinylamino-pyrimido[4,5-b][1,4]diazepines (28–33)a–g.

Figure 2

Bar chart of the mean growth percent (MGP) against 60 cancer cell lines for the trisubstituted triazines 14–15 and 17–18, chalcones (20,21)a–g and (23,24)a–g, and diazepines (28–33)a–g.

Figure 3

Bar chart of the In vitro Minimum Inhibitory Concentration (MIC) values for the triazinylamino-chalcones 24a–g and triazinyloxy- and triazinylamino-pyrimido[4,5-b][1,4]diazepines 29a–g and 31a–g, against M. tuberculosis ATCC 27294. Control: Isoniazid (0.1 µg/mL).