Synthesis and Antiprotozoal Activities of New 3-Azabicyclo 3

Supplementary material:

Including spectraldata of compounds 4d-4i, 5b, 6b and 7d-7i, 8b, 9b

The antiprotozoal potencies of newly prepared 3-azabicyclo[3.2.2]nonanes

Sarfraz Ahmad1, Werner Seebacher2,*, Johanna Faist2, Marcel Kaiser3, Reto Brun3, Robert Saf4, Robert Weis2

1Center for Research in Molecular Medicine, The University of Lahore, Lahore, Pakistan

2Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, A-8010 Graz, Austria

3Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland and University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland

4Institute for Chemistry and Technology of Materials (ICTM), Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria

Corresponding author: Tel.: +43 316 380 8648; fax: +43 316 380 9846. E-mail address: (W. Seebacher)

Running title: Antiprotozoal potencies of new 3-aza-bicyclononanes

(6RS,9RS)-()-2-(Diethylamino)-1-(6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)ethanone (4d)

IR (KBr):= 2956 (s), 2931 (s), 2869 (m), 1640 (s), 1601 (w), 1495 (w), 1450 (m), 1373 (w), 1294 (w), 1236 (w), 1124 (w), 1095 (w), 752 (w), 699 (m) cm-1; UV (CH2Cl2):(log) = 232 (3.627) nm;minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 13.92 (C-4’’), 20.56 (C-3’’), 23.26 ((CH2)2), 28.55 (C-2’’), 32.81 (C-8), 37.89 (C-7), 38.18 (C-9), 42.59 (C-6), 43.12 (C-5), 45.36 (N(CH2)2), 47.98 (C-4), 52.16 (C-2), 53.86 (C-1’’), 57.66 (C-1), 59.22 (C-2’), 126.20, 126.54, 127.72, 128.28, 128.49 (aromatic C), 143.19, 145.46 (aromatic Cq), 171.11 (C-1’) ppm;main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 13.80 (C-4’’), 20.33 (C-3’’), 23.46 ((CH2)2), 28.82 (C-2’’), 31.54 (C-8), 35.86 (C-9), 38.42 (C-7), 44.29 (C-6), 44.81 (C-5), 45.83 (N(CH2)2), 46.15 (C-2), 52.16 (C-4), 53.91 (C-1’’), 57.88 (C-2’), 59.22 (C-1), 126.24, 126.45, 126.63, 126.90, 128.41, 128.64 (aromatic C), 142.36, 145.40 (aromatic Cq), 170.78 (C-1’) ppm.

(6RS,9RS)-()-2-(Diisopropylamino)-1-(6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)ethanone (4e)

IR (KBr):= 2964 (s), 2870 (m), 1637 (s), 1495 (w), 1449 (m), 1364 (w), 1236 (w), 1206 (w), 1172 (w), 1156 (w), 1119 (w), 750 (w), 699 (s) cm-1; UV (CH2Cl2):(log) = 231 (3.644) nm;minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 20.41 (C-2’’), 20.54 (C-2’’), 23.39 ((CH2)2), 33.66 (C-8), 37.60 (C-7), 38.28 (C-9), 42.48 (C-6), 43.15 (C-5), 45.48 (N(CH2)2), 47.94 (C-4), 49.10 (C-1’’), 51.42 (C-2’), 52.87 (C-2), 57.67 (C-1), 126.76, 127.92, 128.46, 128.63 (aromatic C), 143.46, 145.74 (aromatic Cq), 172.40 (C-1’) ppm;main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 19.37 (C-2’’), 20.85 (C-2’’), 23.63 ((CH2)2), 31.79 (C-8), 36.21 (C-9), 38.96 (C-7), 44.59 (C-6), 45.20 (C-5), 45.74 (N(CH2)2), 46.80 (C-2), 48.57 (C-1’’), 50.11 (C-2’), 52.56 (C-4), 58.68 (C-1), 126.34, 126.54, 126.81, 127.21, 128.53, 128.78 (aromatic C), 142.81, 145.94 (aromatic Cq), 172.27 (C-1’) ppm.

(6RS,9RS)-()-1-(6,9-Diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)-2-pyrrolidinoethanone (4f)

IR (KBr):= 2961 (s), 2872 (s), 2793 (m), 1642 (s), 1600 (w), 1495 (m), 1448 (s), 1292 (w), 1235 (w), 1184 (w), 1125 (w), 752 (m), 700 (s) cm-1; UV (CH2Cl2):(log) = 232 (3.594) nm; minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 23.73 (C-2’’, (CH2)2), 32.81 (C-8), 37.84 (C-7), 38.22 (C-9), 42.71 (C-6), 43.12 (C-5), 45.61 (N(CH2)2), 47.92 (C-4), 52.27 (C-2), 54.05 (C-1’’), 58.40 (C-1), 59.76 (C-2’), 126.35, 126.39, 126.69, 127.81, 128.48, 128.64 (aromatic C), 143.28, 145.48 (aromatic Cq), 170.55 (C-1’) ppm; main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 23.55, 23.65 (C-2’’, (CH2)2), 31.76 (C-8), 36.24 (C-9), 38.13 (C-7), 44.20 (C-6), 44.98 (C-5), 46.13 (N(CH2)2), 46.28 (C-2), 51.18 (C-4), 54.05 (C-1’’), 57.75 (C-2’), 59.76 (C-1), 126.47, 126.65, 126.75, 127.22, 128.58, 128.80 (aromatic C), 142.40, 145.24 (aromatic Cq), 169.87 (C-1’) ppm.

(6RS,9RS)-()-1-(6,9-Diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)-2-piperidinoethanone (4g)

IR (KBr):= 2934 (s), 2853 (w), 1640 (s), 1495 (w), 1450 (m), 1303 (w), 1122 (w), 751 (w), 699 (m) cm-1; UV (CH2Cl2):(log) = 231 (3.556) nm; minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 23.64 ((CH2)2), 23.76 (C-3’’), 25.48 (C-2’’), 32.90 (C-8), 37.69 (C-7), 37.92 (C-9), 42.52 (C-6), 43.01 (C-5), 45.72 (N(CH2)2), 47.83 (C-4), 52.32 (C-2), 54.65 (C-1’’), 58.13 (C-1), 63.41 (C-2’), 126.22, 126.29, 126.62, 127.63, 128.34, 128.55 (aromatic C), 143.21, 145.49 (aromatic Cq), 170.33 (C-1’) ppm; main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 23.59((CH2)2), 23.82 (C-3’’), 25.65 (C-2’’), 31.68 (C-8), 36.11 (C-9), 38.07 (C-7), 44.06 (C-6), 44.84 (C-5), 46.04 (N(CH2)2), 46.34 (C-2), 51.34 (C-4), 54.50 (C-1’’), 59.49 (C-1), 61.34 (C-2’), 126.37, 126.54, 126.68, 127.13, 128.48, 128.70 (aromatic C), 142.37, 145.23 (aromatic Cq), 169.63 (C-1’) ppm; HRMS (EI+): calcd C31H41N3O [M+]: 471.3250; found: 471.3270.

(6RS,9RS)-()-2-(4-Methylpiperazin-1-yl)-1-(6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)ethanone (4h)

IR (KBr):= 2934 (s), 2871 (m), 2793 (s), 1640 (s), 1495 (w), 1450 (s), 1291 (m), 1162 (m), 1134 (m), 1012 (w), 751 (w), 699 (s) cm-1; UV (CH2Cl2):(log) = 232 (3.630) nm; minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 23.63((CH2)2), 32.93 (C-8), 37.87 (C-7), 38.03 (C-9), 42.56 (C-6), 43.02 (C-5), 45.74 (N(CH2)2), 45.90 (C-3’’), 47.80 (C-4), 52.67 (C-2), 53.44 (C-1’’), 54.67 (C-2’’), 57.82 (C-1), 62.35 (C-2’), 126.31, 126.37, 126.70, 127.72, 128.44, 128.63 (aromatic C), 143.34, 145.61 (aromatic Cq), 169.77 (C-1’) ppm; main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 23.54((CH2)2), 31.70 (C-8), 36.42 (C-9), 38.85 (C-7), 44.27 (C-6), 45.02 (C-5), 45.66 (N(CH2)2), 45.90 (C-3’’), 46.64 (C-2), 51.28 (C-4), 53.38 (C-1’’), 54.74 (C-2’’), 58.32 (C-1), 60.41 (C-2’), 126.42, 126.54, 126.73, 127.27, 128.55, 128.76 (aromatic C), 142.77, 145.71 (aromatic Cq), 168.91 (C-1’) ppm.

(6RS,9RS)-()-1-(6,9-Diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (4i)

IR (KBr):= 2923 (m), 2869 (w), 1640 (s), 1495 (w), 1450 (m), 1113 (w), 749 (m), 699 (m) cm-1; UV (CH2Cl2):(log) = 232 (3.672) nm; minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 23.57 ((CH2)2), 28.76 (C-4’’), 32.34 (C-8), 38.06 (C-7), 38.26 (C-9), 42.83 (C-6), 43.10 (C-5), 45.82 (N(CH2)2), 48.46 (C-4), 50.85 (C-3’’), 52.54 (C-2), 56.17 (C-1’’), 58.43 (C-1), 62.29 (C-2’), 125.65, 126.23, 126.27, 126.62, 126.63, 127.76, 128.70 (aromatic C), 133.65, 134.04, 143.21, 145.39 (aromatic Cq), 170.18 (C-1’) ppm; main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 23.68 ((CH2)2), 28.90 (C-4’’), 32.04 (C-8), 36.16 (C-9), 38.26 (C-7), 44.16 (C-6), 44.89 (C-5), 46.04 (N(CH2)2), 46.72 (C-2), 50.85 (C-3’’), 51.68 (C-4), 55.68 (C-1’’), 59.18 (C-1), 60.69 (C-2’), 125.50, 126.04, 126.38, 126.47, 126.79, 127.24, 128.52, 128.58, 128.78 (aromatic C), 133.91, 134.33, 142.60, 145.39 (aromatic Cq), 169.49 (C-1’) ppm.

(6RS,9RS)-()-3-(Diethylamino)-1-(6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)propan-1-one (5b)

IR (KBr):= 2966 (s), 2932 (s), 2871 (m), 2806 (w), 1641 (s), 1495 (w), 1449 (s), 1372 (w), 1199 (w), 1137 (w), 750 (w), 700 (s) cm-1; UV (CH2Cl2):(log) = 231 (3.607) nm; minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 11.71 (C-2’’), 23.40 ((CH2)2), 32.34 (C-2’), 32.57 (C-8), 37.83 (C-7), 38.30 (C-9), 42.69 (C-6), 43.35 (C-5), 45.53 (N(CH2)2), 47.02 (C-1’’), 47.50 (C-4), 48.80 (C-3’), 52.64 (C-2), 57.91 (C-1), 126.32, 126.34, 126.67, 127.86, 128.61 (aromatic C), 143.22, 145.52 (aromatic Cq), 171.91 (C-1’) ppm; main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 11.66 (C-2’’), 23.49 ((CH2)2), 31.16 (C-2’), 31.54 (C-8), 36.57 (C-9), 39.12 (C-7), 44.43 (C-6), 45.03 (C-5), 45.60 (N(CH2)2), 46.24 (C-2), 46.86 (C-1’’), 48.32 (C-3’), 51.57 (C-4), 58.04 (C-1), 126.40, 126.53, 126.70, 127.20, 128.47, 128.75 (aromatic C), 142.70, 145.72 (aromatic Cq), 171.61 (C-1’) ppm.

(6RS,9RS)-()-4-(Diethylamino)-1-(6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonan-3-yl)butan-1-one (6b)

IR (KBr):= 2966 (s), 2933 (s), 2871 (m), 2803 (w), 1643 (s), 1495 (w), 1449 (s), 1431 (s), 1372 (w), 1232 (w), 1199 (w), 1136 (w), 751 (w), 700 (s) cm-1; UV (CH2Cl2):(log) = 232 (3.641) nm; minor constituent (E)-form:13C NMR (CDCl3, 100 MHz):  = 11.73 (C-2’’), 22.62 (C-3’), 23.43 ((CH2)2), 31.96 (C-8), 32.34 (C-2’), 37.96 (C-7), 38.33 (C-9), 42.81 (C-6), 43.40 (C-5), 45.52 (N(CH2)2), 46.74 (C-1’’), 47.57 (C-4), 52.18 (C-4’), 52.53 (C-2), 57.95 (C-1), 126.27, 126.29, 126.63, 127.83, 128.56 (aromatic C), 143.22, 145.53 (aromatic Cq), 172.68 (C-1’) ppm; main component (Z)-form:13C NMR (CDCl3, 100 MHz):  = 11.66 (C-2’’), 21.91 (C-3’), 23.43 ((CH2)2), 31.40 (C-2’), 31.57 (C-8), 36.74 (C-9), 39.06 (C-7), 44.38 (C-6), 45.24 (C-5), 45.52 (N(CH2)2), 46.34 (C-2), 46.57 (C-1’’), 51.56 (C-4), 51.95 (C-4’), 57.95 (C-1), 126.32, 126.46, 126.66, 127.30, 128.40, 128.70 (aromatic C), 142.75, 145.77 (aromatic Cq), 172.46 (C-1’) ppm.

(6RS,9RS)-()-3-(2-Dibutylaminoethyl)-6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonane (7d)

IR (KBr):= 2955 (s), 2929 (s), 2870 (s), 2801 (s), 1601 (w), 1494 (m), 1453 (m), 1376 (w), 1314 (w), 1148 (w), 1118 (m), 1032 (w), 748 (m), 699 (s) cm-1; UV (CH2Cl2):(log) = 231 (3.693) nm; 13C NMR (CDCl3, 100 MHz):  = 14.13 (C-4’’), 20.76 (C-3’’), 23.54((CH2)2), 29.30 (C-2’’), 35.02 (C-8), 38.07 (C-7), 39.36 (C-9), 44.78 (C-5), 44.98 (C-6), 45.38 (N(CH2)2), 52.08 (C-2’), 54.35 (C-1’’), 56.30 (C-1’), 58.31 (C-1), 59.20 (C-2), 60.74 (C-4), 125.96, 126.07, 126.85, 128.04, 128.52, 128.78 (aromatic C), 145.22, 146.76 (aromatic Cq) ppm.

(6RS,9RS)-()-3-(2-Diisopropylethyl)-6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonane (7e)

IR (KBr):= 2963 (s), 2928 (s), 2871 (m), 2803 (m), 1494 (m), 1451 (w), 1378 (w), 1361 (w), 1205 (w), 1157 (m), 1116 (m), 749 (w), 699 (s) cm-1; UV (CH2Cl2):(log) = 231 (3.726) nm; 13C NMR (CDCl3, 100 MHz):  = 20.70 (C-2’’), 23.54 ((CH2)2), 34.88 (C-8), 37.93 (C-7), 39.39 (C-9), 43.44 (C-2’), 44.85 (C-5), 45.00 (C-6), 45.33 (N(CH2)2), 49.26 (C-1’’), 58.18 (C-1), 59.52 (C-2), 60.54 (C-1’), 60.74 (C-4), 125.93, 126.02, 126.83, 127.98, 128.49, 128.78 (aromatic C), 145.29, 146.86 (aromatic Cq) ppm.

(6RS,9RS)-()-6,9-Diphenyl-1-pyrrolidino-3-(2-pyrrolidinoethyl)- 3-azabicyclo[3.2.2]nonane (7f)

IR (KBr):= 2961 (s), 2873 (m), 2788 (s), 1600 (w), 1494 (m), 1451 (m), 1348 (w), 1314 (w), 1149 (w), 1117 (m), 749 (m), 699 (s) cm-1; UV (CH2Cl2):(log) = 232 (3.709) nm; 13C NMR (CDCl3, 100 MHz):  = 23.40 (C-2’’), 23.52 ((CH2)2), 35.08 (C-8), 38.05 (C-7), 39.29 (C-9), 44.74 (C-5), 44.95 (C-6), 45.25 (N(CH2)2), 54.08 (C-2’), 54.35 (C-1’’), 57.31 (C-1’), 58.06 (C-1), 59.14 (C-2), 60.66 (C-4), 125.86, 125.98, 126.79, 127.97, 128.45, 128.69 (aromatic C), 145.19, 146.77 (aromatic Cq) ppm;

(6RS,9RS)-()-6,9-Diphenyl-3-(2-piperidinoethyl)-1-pyrrolidino-3-azabicyclo[3.2.2]nonane (7g)

IR (KBr):= 2932 (s), 2852 (m), 2800 (s), 1494 (m), 1451 (m), 1352 (w), 1304 (w), 1152 (w), 1123 (m), 748 (m), 699 (s) cm-1; UV (CH2Cl2):(log) = 231 (3.689) nm; 13C NMR (CDCl3, 100 MHz):  = 23.49((CH2)2), 24.33 (C-3’’), 25.95 (C-2’’), 34.95 (C-8), 38.13 (C-7), 39.22 (C-9), 44.77 (C-5), 44.95 (C-6), 45.20 (N(CH2)2), 54.88 (C-1’’), 55.53 (C-1’), 56.94 (C-2’), 58.02 (C-1), 58.70 (C-2), 60.80 (C-4), 125.80, 125.92, 126.74, 127.91, 128.39, 128.61 (aromatic C), 145.14, 146.71 (aromatic Cq) ppm.

(6RS,9RS)-()-3-[2-(4-Methylpiperazin-1-yl)ethyl]-6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonane (7h)

IR (KBr):= 2935 (s), 2872 (m), 2793 (s), 1494 (m), 1452 (m), 1354 (w), 1283 (m), 1164 (s), 1118 (m), 1013 (m), 748 (m), 699 (s) cm-1; UV (CH2Cl2):(log) = 232 (3.668) nm;13C NMR (CDCl3, 100 MHz):  = 23.50((CH2)2), 34.89 (C-8), 38.19 (C-7), 39.21 (C-9), 44.71 (C-5), 44.97 (C-6), 45.25 (N(CH2)2), 46.03 (C-3’’), 53.49 (C-1’’), 55.11 (C-2’’), 55.42 (C-1’), 56.12 (C-2’), 58.02 (C-1), 58.75 (C-2), 60.79 (C-4), 125.88, 126.00, 126.79, 127.99, 128.46, 128.62 (aromatic C), 145.15, 146.71 (aromatic Cq) ppm.

(6RS,9RS)-()-6,9-Diphenyl-1-pyrrolidino-3-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-3-azabicyclo[3.2.2]nonane (7i)

IR (KBr):= 2924 (s), 2800 (s), 1600 (w), 1494 (m), 1452 (m), 1351 (w), 1314 (w), 1119 (m), 1097 (m), 937 (w), 741 (s), 699 (s) cm-1; UV (CH2Cl2):(log) = 232 (3.766) nm; 13C NMR (CDCl3, 100 MHz):  = 23.54 ((CH2)2), 29.19 (C-4’’), 35.04 (C-8), 38.19 (C-7), 39.33 (C-9), 44.79 (C-5), 45.03 (C-6), 45.30 (N(CH2)2), 51.28 (C-3’’), 55.85 (C-1’), 56.14 (C-2’), 56.48 (C-1’’), 58.10 (C-1), 59.05 (C-2), 60.84 (C-4), 125.52, 125.92, 126.05, 126.48, 126.84, 128.02, 128.51, 128.58, 128.70 (aromatic C), 134.25, 134.80, 145.18, 146.78 (aromatic Cq) ppm.

(6RS,9RS)-()-3-(3-Diethylaminopropyl)-6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonane (8b)

IR (KBr):= 2965 (s), 2872 (m), 2801 (s), 1601 (w), 1494 (m), 1451 (m), 1381 (w), 1316 (w), 1201 (w), 1149 (w), 1121 (m), 1070 (w), 749 (m), 699 (s) cm-1; UV (CH2Cl2):(log) = 233 (3.669) nm; 13C NMR (CDCl3, 100 MHz):  = 11.61 (C-2’’), 23.42 ((CH2)2), 24.82 (C-2’), 35.14 (C-8), 38.18 (C-7), 39.16 (C-9), 44.64 (C-5), 44.92 (C-6), 45.20 (N(CH2)2), 46.87 (C-1’’), 51.41 (C-3’), 56.58 (C-1’), 57.85 (C-1), 58.19 (C-2), 60.73 (C-4), 125.85, 125.97, 126.80, 127.98, 128.44, 128.56 (aromatic C), 145.18, 146.72 (aromatic Cq) ppm.

(6RS,9RS)-()-3-(3-Diethylaminobutyl)-6,9-diphenyl-1-pyrrolidino-3-azabicyclo[3.2.2]nonane (9b)

IR (KBr):= 2965 (s), 2931 (s), 2870 (m), 2800 (s), 1601 (w), 1494 (m), 1452 (m), 1381 (w), 1292 (w), 1201 (w), 1149 (w), 1115 (m), 1070 (w), 749 (m), 699 (s) cm-1; UV (CH2Cl2):(log) = 232 (3.708) nm; 13C NMR (CDCl3, 100 MHz):  = 11.64 (C-2’’), 23.40((CH2)2), 24.93, 25.24 (C-2’, C-3’), 35.06 (C-8), 38.19 (C-7), 39.21 (C-9), 44.65 (C-5), 44.88 (C-6), 45.18 (N(CH2)2), 46.76 (C-1’’), 52.73 (C-4’), 57.87 (C-1), 58.09 (C-2), 58.18 (C-1’), 60.63 (C-4), 125.81, 125.93, 126.76, 127.94, 128.40, 128.56 (aromatic C), 145.19, 146.71 (aromatic Cq) ppm;