Herein, we designed and synthesized certain anilinoquinazoline derivatives bearing bulky arylpyridinyl, arylpropenoyl and arylpyrazolyl moieties at the 4' position of the anilinoquinazoline, as potential dual HER2/EGFR kinase inhibitors. A detailed molecular modeling study was performed by docking the synthesized compounds in the active site of the epidermal growth factor receptor (EGFR). The synthesized compounds were further tested for their inhibitory activity on EGFR and HER2 tyrosine kinases. The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR with IC50 equal to 2.09 and 1.94 μM, respectively, and with IC50 equal to 3.98 and 1.04 μM on HER2, respectively. Furthermore, the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines, known to overexpress EGFR, showed an IC50 range of 2.4 and 2.5 μM, respectively.

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Literature surveys indicate that quinoline derivatives possess diverse pharmacological activities, including antimicrobial (1), antimalarial (2), antiviral (3), antitumor (4), immunomodulatory (5), caspase-3 inhibition (6), antileishmanial (7), local anesthetic (8), antiarrhythmic (8) and anti-inflammatory activities (9). Also, thiosemicarbazones constitute one of the most versatile classes of compounds possessing a wide spectrum of activities. It has been reported that thiosemicarbazone derivatives possess antimicrobial (1, 10), antimalarial (11), antiamoebic (12) and antitumor (13) activities. They have been in the focus of interest of medicinal chemists in the past decades because of the outstanding biological activities exhibited by several derivatives incorporating the heterocyclic moiety. Similarly, it is well documented that thiazoline nucleus is associated with a vari- 5-Acyl-8-hydroxyquinoline-2-(3'-substituted-4'-aryl-2,3--dihydrothiazol-2'-ylidene)hydrazones, 5a-e to 10a-c, were prepared by the reaction of appropriate 5-acyl-8-hydroxyquinoline-4-substituted thiosemicarbazones 3a-e and phenacyl bromides 4a-e. Structures of the new compounds were verified on the basis of spectral and elemental analyses. Twenty-eight new compounds were tested for their possible antimicrobial activities. Most of the tested compounds showed weak to moderate antibacterial activity against most of the bacterial strains used in comparison with gatifloxacin as a reference drug. The test compounds showed weak to moderate antifungal activity against tested fungi in comparison with ketoconazole as a reference drug. On the other hand, the newly synthesized compounds were tested for their anti-inflammatory effects and most of them showed good to excellent anti-inflammatory activity compared to indomethacin. Moreover, ulcerogenicity and the median lethal dose (LD 50 ) of the most active anti-inflammatory compounds 6b and 9e were determined in mice; they were non-toxic at doses up to 400 mg kg -1 after i.p. administration.

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In the present study, a series of 2-aroylindole derivatives were synthesized by phase transfer catalysis (PTC) and were characterized by IR, 1 H-NMR, Mass spectral and Elemental analysis. Indole derivatives 6a-g, 7a-f, 8a-f and 9a-13a were tested for analgesic activity using hot-plate test. Compounds 7b and 8b were tested for antipyretic and anti-inflammatory activity using yeast induced hyperthermia and paw edema in rats. Analgesic activity was shown when indole nucleus was substituted at position 2 and 3 by phenyl and (p-halo)benzoyl moieties respectively, where highest activity was recognised in compounds 7b and 8b. Both compounds also exhibited faster, more effective and prolonged reduction in hyperthermia and edema induced in rats compared with indomethacin. Compounds 7b and 8b were also tested for ulcerogenic activity in mice, where a lower ulcerogenic effect was observed compared with indomethacin at all tested dose levels.