We demonstrate that a focused library based on truncated, cross-linked interfacial peptides of HIV-1 protease produces effective dimerization inhibitors of the enzyme. By combining individual changes of the library into a single compound, we obtained a significantly more potent agent and found that an additive increase in inhibitor efficacy was obtained. The good activity of library members against an active-site drug-resistant protease mutant bodes well for dimerization inhibition as a complementary method to targeting the active site.

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In the preceeding we reported the synthesis and biological properties of carbapenems having various (substituted) pyrrolidin-3-ylthio groups at C-2. In this study a series of 1 P-methyl carbapenems having a thiazolo [3,2-a] benzimidazole moiety at the C-2 position were synthesized and their in vitro antibacterial activities were tested.Reaction of 2-mercaptobenzimidazole (1) with 1,3-dichloroacetone in acetone gave l-(benzimidazolyl-2-thio)-3chloro-2-propanon hydrochloride. Cyclization of this compound in sulfuric acid followed by basic work up provides compound 2 in moderate yield3). Treatment of 2 with potassium thioacetate in DMF and toluene gave 3-(acetylthiomethyl)-thiazolo[3,2-a]benzimidazole (3). Finally the acetylthio group of 3 was readily hydrolyzed with 4N-NaOH in methanol to give 3-(mercaptomethyl)-thiazolo[3,2-a]benzimidazole (4) (Scheme 1). 2LCl a? SAC Scheme 1Preparation of the 2-(diphenylphosphory1oxy)carbapenem compound 5 has been reported4). Reaction of 5 with 4 in the presence of diisopropylethylamine provided the 2-substituted carbapenem 6 . The corresponding quaternary ammonium salt was obtained by methyl iodide at room temp. The synthesis of the final compound 7, 8 was completed by catalytic hydrogenolysis over 10% Pd/C in the presence of phosphate buffer (pH = 7). Compounds 9-14 were prepared analogously. Antibacterial activityThe minimum inhibitory concentration (MIC) of the new carbapenem compounds 7-14 were determined by an agar 7 Scheme 2 dilution method using Mueller-Hinton agar ( Table 1). The effect of the substituents on the thiazolobenzimidazole ring was investigated.Compound 11 having a nitro group exhibits inferior antibacterial activity compared to compound 7 against both Gram-positive and Gram-negative bacteria. In general, the basicity of the substituent was observed to affect the activity considerably5). Compounds having the quaternary ammonium salt moiety 8, 10, 12, 14 possess an increased activity against Escherichia coli and Enterobacter cloacae as compared to compounds 7,9,11,13. Experimental PartMelting points: Thomas Hoover apparatus, uncorrected.-UV-spectra: Hewlett-Packard 8451A UV-VIS spectrophotometer.-'H-NMR spectra: Varian Gemini 300 spectrometer, tetramethylsilane as internal standard. 3-(Chloromethyl)-rhiazolo[3,2-a]benzimidazole (2)To a solution of 2-mercaptobenzimidazole (1) (3.0 g, 20 mmol) in acetone (50 ml) at room temp. was added slowly 1,3-dichloroacetone (5.80 g, 45.7 mmol). After 10 min the reaction mixture was heated to 40°C for 2 h. The precipitate was washed with acetone and ethanol. The mixture of the above solid in 20 ml of conc. H2S04 was stored at room temp. for 20 h, Arch. Pharm. (Weinheim) 328,289-291 (1995) 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1995 0365-6233/95/0303-0289 $5.00 + .25/0