Preliminary communication Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents ✩ Samia M. Rida a , Fawzia A. Ashour a , Soad A.M. El-Hawash a, *, Mona M. ElSemary a , Mona H. Badr a , Manal A. Shalaby b a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt b Genetic Engineering and Biotechnology Research Department, Mubarak City for Scientific Research and Technology Application, New Borg El-Arab, Alexandria, Egypt Received 30 September 2004; received in revised form 11 March 2005; accepted 13 March 2005 Available online 22 July 2005 Abstract In an effort to establish new candidates with improved antineoplastic, anti-HIV-1 and antimicrobial activities we report here the synthesis and in vitro biological evaluation of various series of 2-substituted benzoxazoles: 2-[(Arylhydrazono, arylidene, cycloalkylidene and N-substituted thiocarbamoyl)cyanomethyl]-benzoxazoles(2–4 and 7, respectively); 2-[(4- or 5-oxothiazoliden-2-yliden)benzoxazoles (5 and 6) and 2-(4-amino-3-substituted-2-thioxo-2,3-dihydrothiazol-5-yl)benzoxazoles (8), together with the synthesis of some substituted 3H-pyrido[2,1-b]benzoxazoles (9–11). The absolute configuration of compound 3b was determined by X-ray crystallography. The results of the in vitro anticancer screening revealed that some of the tested compounds exhibited broad spectrum antitumor activity. The most active compounds are 2a, 3b, 8a and 8d, their GI 50 MG-MID values: 37.7, 19.1, 20.0 and 15.8 μM; TGI MG-MID values: 75.9, 53.7, 53.7, and 58.9 μM; and LC 50 MG-MID values: 97.7, 93.3, 89.1and 93.3 μM, respectively. The in vitro microbiological data showed that compound 7c was the most active against Staphylococcus aureus (minimal inhibitory concentration (MIC) < 12.5 μg ml –1 ). While compounds 5, 8a, and 8d were the most active against Bacillus subtilis (MIC values < 12.5 μg ml –1 ). On the other hand, compounds 5 and 7c were the most active against Escherichia coli (MIC < 25 μg ml –1 ), their activity is about half the activity of ampicillin and streptomycin . In addition, compound 4b and 7c were the most active against Pseudomonas aeruginosa (MIC < 25, 50 μg ml –1 ). Compound 4b was two times as active as ampicillin and streptomycin while compound 7c was active as both. The results of antimycotic activity indicated that, Compound 7c showed mild activity against Candida albicans when compared with clotrimazole (MIC < 100 μg ml –1 ). In vitro HIV-1 testing revealed that compound 7a dis- played moderate anti-HIV-1 activity (maximum % cell protection, 36.6 at 2 × 10 -5 μM). © 2005 Elsevier SAS. All rights reserved. Keywords: 2-Cynomethylbenzoxazole; 2-Arylidenecynomethylbenzoxazoles; 2-Hydrazonocynomethylbenzoxazoles; 2-(2,3-Dihydrothiazol-5-yl)benzoxazoles; 2-Thiocarbamoylcyanomethylbenzoxazoles; 3H-pyrido[2,1-b]benzoxazoles; Anticancer; Anti-HIV-1; Antimicrobial activity 1. Introduction In the last few years various 2-substituted benzoxazole derivatives were studied extensively for their antitumor [1–7], antiviral [8–14] and antimicrobial activities [15–23] as non- nucleoside topoisomerase 1 poison, HIV-1 reverse tran- scriptase and/or DNA gyrase inhibitors [12–14]. For example the antibiotic Calcimycin that includes a 2-substituted ben- zoxazole ring in its molecular structure is very active against Bacillus cereus, Bacillus megaterium, and Micrococcus lutes [15]. The benzoxazole derivative, 3-(4,7-dichlorobenzoxazol- 2-ylmethylamino)-5-ethyl-6-methyl-pyridin-2-(1H)-one (L-697.661, Fig. 1) was found to be an effective non- nucleoside selective HIV-1 reverse transcriptase inhibitor.A combined therapy with zidovudine and L-697.661 achieved marked decrease of viremia in some primary HIV-infected patients [12–14]. > This work is partly presented in Assiut University, Fourth Pharmaceuti- cal Sciences Conference, Faculty of Pharmacy,Assiut University, 6–7 March 2004, pp. 99–100. * Corresponding author. Tel.: +20 3 487 3273. E-mail address: soadhawash@yahoo.com (S.A.M. El-Hawash). European Journal of Medicinal Chemistry 40 (2005) 949–959 www.elsevier.com/locate/ejmech 0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmech.2005.03.023