Benzofuran moiety is the main component of many biologically active natural and synthetic heterocycles.

Indolizines are structural isomers with indoles. Although several indole-based commercial drugs are available in the market, none of the indolizine-based drugs are available up to-date. Natural and...

Due to the importance of the fluorinated heterocycles as main components of marketed drugs where 20% of the anticancer and antibiotic drugs contain fluorine atoms, this review describes the reported five-membered heterocycles and their benzo-fused systems having directly connected fluorine atom(s). The in vivo and in vitro anticancer and antimicrobial activities of these fluorinated heterocycles are well reported. Some fluorinated heterocycles were found to be lead structures for drug design developments where their activities were almost equal to or exceeded the potency of the reference drugs. In most cases, the fluorine-containing heterocycles showed promising safety index via their reduced cytotoxicity in non-cancerous cell lines. SAR study assigned that fluorinated heterocycles having various electron-donating or electron-withdrawing substituents significantly affected the anticancer and antimicrobial activities.

A number of new 1,ω-bis((acetylphenoxy)acetamide)alkanes 5a–f were prepared then their bromination using NBS furnished the novel bis(2-bromoacetyl)phenoxy)acetamides 6a–f. Reaction of 6a–f with 4-amino-5-substituted-4H-1,2,4-triazole-3-thiol 7a–d and with o-phenylenediamine derivatives 9a and b afforded the corresponding bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a–l and bis(quinoxaline) derivatives 10a–e in good yields. The cytotoxicity of the synthesized compounds as well as apoptosis induction through PARP-1 and EGFR as molecular targets was evaluated. Three compounds, 8d, 8i and 8l, exhibited much better cytotoxic activities against MDA-MB-231 than the drug Erlotinib. Interestingly, compound 8i induced apoptosis in MDA-MB-231 cells by 38-fold compared to the control arresting the cell cycle at the G2/M phase, and its treatment upregulated P53, Bax, caspase-3, caspase-8, and caspase-9 gene levels, while it downregulated the Bcl2 level. Compound 8i exhibited promising dual enzyme inhibition of PARP-1 (IC₅₀ = 1.37 nM) compared to Olaparib (IC₅₀ = 1.49 nM), and EGFR (IC₅₀ = 64.65 nM) compared to Erlotinib (IC₅₀ = 80 nM). These results agreed with the molecular docking studies that highlighted the binding disposition of compound 8i inside the PARP-1 and EGFR protein active sites. Hence, compound 8i may serve as a potential anti-breast cancer agent.

New bis(β-difunctional) compounds could be prepared in good yields. Their utility as intermediates in the synthesis of novel bis(heterocycles) were also investigated.