Design and synthesis of new potent anticancer benzothiazole amides and ureas featuring pyridylamide moiety and possessing dual B-RafV600E and C-Raf kinase inhibitory activities

Predictive QSAR model and clustering analysis of some Benzothiazole derivatives as cytotoxic inhibitors

“…The cytotoxic activities of Benzothiazole derivatives were evaluated in the human cancer cell lines SK-BR3 [34]. The growth inhibition (IC 50 ) was converted in pIC 50 by taking logarithm (pIC 50 = -Log(IC 50 )) which was taken as the dependent parameter for QSAR study.…”

Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity

“…In the present study,w ea imed at performing further structural modifications in terms of the hydrophobic tail, in an attempt to improve the anticancer activity of the ureidobenzothiazole A. [17] We thought that replacing the small lipophilic chlorine atom of A with either (morpholin-1-yl)methyl 5 or (4ethylpiperazin-1-yl)methyl moiety 6 ( Figure 1) mayi mprove the physicochemical properties of compound A and hence its cellular potency.From another perspective,itwas worthy to investigatethe impactofstructural extension in the hydrophobic tail fragment on the affinity towardv ariousp rotein kinases. In the light of thesec onsiderations,t wo new benzothiazoles 5 and 6 have been designed, synthesized,a nd evaluated for their anticancer activities over ap anel of 60 human cancerc ell lines.…”

“…[14] Accordingly,s orafenib structure could be dissected into the head pyridine moiety as hinge region binder,c entral phenyl ring linker,u rea as hydrogen bond donor/acceptor pair, and ah ydrophobic tail (4-chloro-3-trifluoromethylphenyl terminal) that access the hydrophobic pocket createdb yt he flip of the DFG motif of the kinase activation loop. [15] Recently,w er eported as eries of 2-ureidoquinolines [16] and ureidobenzothiazoles [17] derivatives as sorafenib congeners by replacing the central phenyl linker of sorafenib with either quinolone [16] or benzothiazole [17] scaffold, while conserving the other structural features. Interestingly,s uch modifications led to considerable improvement in the cellular anticancer potency as well as favorable inhibitory activity towardB -Raf V600E and C-Raf kinases.…”

“…As illustrated in Scheme 1, in order to preparet he target compounds, we synthesized the two main buildingb locks 3a, 3b and 4. [17,18] The anilines 3a and 3b were prepared in three steps. First, a-bromination of 1-methyl-4-nitro-2-(trifluoromethyl)benzenew ith N-bromosuccinimide (NBS) in the presence of azobisisobutyronitrile( AIBN) afforded the corresponding bromo derivative 1 in 63 %y ield.…”

“…[19] Nucleophilic substitution of 1 with morpholine or 4-ethylpiperazine using K 2 CO 3 as ab ase in dichloromethane produced the alkylated nitro derivatives 2a and 2b,w hichu nderwent reduction with Pd/C under hy-drogen atmosphere to yield the corresponding anilines 3a and 3b.O nt he other hand, the 2-aminobenzothiazole derivative 4 was prepared adoptingo ur previously reported method. [17,18] Treatmento ft he benzothiazol-2-yl amine 4 with 1,1'-carbonyldiimidazole (CDI) in DMF at room temperature produced the corresponding isocyanate.I nt he same pot, the appropriate aniline 3a or 3b was added and the reaction mixture was heated at 100 8Cf or 3hto afford the desired ureidobenzothiazoles 5 and 6.…”