Abstract
Based on the hybrid pharmacophore design concept, a novel series of dual diaryl urea and N-acylhydrazone derivatives were synthesized and evaluated for their in vitro cytotoxicity by the standard MTT assay. The pharmacological results indicated that most compounds exhibited moderate to excellent activity. Moreover, compound 2g showed the most potent cytotoxicity against HL-60, A549 and MDA-MB-231 cell lines, with IC50 values of 0.22, 0.34 and 0.41 μM, respectively, which was 3.8 to 22.5 times more active than the reference compounds sorafenib and PAC-1. The promising compound 2g thus emerges as a lead for further structural modifications.
Highlights
Design of single chemical compounds that simultaneously modulate multiple biological targets in a specific manner is the current focus of new drug development and is becoming more popular
All target compounds 1a–g, 2a–k, 3a–e and 4a–c were evaluated for their cytotoxicity in vitro against the human leukemia cell line (HL-60), human lung adenocarcinoma epithelial cell line (A549)
Phenyl groups Ar2 substituted with chromenyl and imidazolidinyl moieties gave rise to two series of compounds 3a–e and 4a–c with a dramatic decrease or even a loss in antitumor potency, indicating that Ar2 was critical for the optimal activity and it is not tolerant ofr bulky and rigid heteroaromatic rings in this region
Summary
Design of single chemical compounds that simultaneously modulate multiple biological targets in a specific manner is the current focus of new drug development and is becoming more popular. Sorafenib (Figure 1), a diaryl urea analogue [1], is a small molecular inhibitor of several tyrosine protein kinases (VEGFR, PDGFR and B-Raf) [2,3] and unique in targeting the. PAC-1 (Figure 1), the first preferential small molecule procaspase-3 activating compound with N-acylhydrazone pharmacophore, is promising as a new anti-tumor drug that can directly influence the apoptotic machinery or suicide of cells and has shown good results in mouse models [7,8,9]. In an attempt to discover new antitumor agents with multiple molecular mechanisms, we combined the diaryl urea moiety from sorafenib and N-acylhydrazone based in a hybrid pharmacophore design. 2-Hydroxyl substitution was retained for the Ar2 ring for the reason that only with the hydroxyl group on Ar2 did the PAC-1 derivatives display antitumor activity in vitro [11]. Ar2 was replaced with a substituted chromenonyl or imidazolindionyl groups, which are often associated with a variety of biological activity, to note the effect of each discreet change on the biological activity of the resulting compounds
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