Indolo[3,2-c]cinnolines with antiproliferative, antifungal, and antibacterial activity.

A series of indolo[3,2-c]cinnoline derivatives was prepared and tested to evaluate their biological activity. Most of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations, whereas none of the compounds were active against HIV-1. With the exception of Scheme 1, Table 1, Table 3 ;  Table 4 Scheme 1.  (a) RR1R2H; (b) RR2H, R1Cl; (c) RR1H, R2Cl; (d) RR1H, R2Me; (e) ROMe, R1R2H (f) RCl, R1R2H; (g) RBr, R1R2H; (h) RNO2, R1R2H; (i) RNO2, R1Cl, R2H. Figure options Download full-size image Download high-quality image (52 K) Download as PowerPoint slide Table 1. Antiproliferative activity of indolo[3,2-c]cinnolines IC50 [μM]a Cell lines 7a 7b 7c 7d 7e 7f 7g 7h 7i Doxo Leukemia/lymphoma L1210 12 1.0 3.5 30 50 24 >100 0.3 ND 0.23 Wil2-NS 4.5 0.5 1.0 20 10 18 89 0.2 1.1 0.02 CCRF-SB 5 0.7 2.8 21 3.2 27 >100 0.2 1.1 0.01 Raji 6.8 0.8 17 >10 12 >10 >100 1.2 1.8 0.08 CCRF-CEM 5 0.5 1.9 10 7.3 5.0 54 0.08 2.2 0.10 MOLT-4 3.3 0.4 1.6 12 3.2 12 >100 0.08 0.2 0.03 MT-4 2.2 0.9 4.7 25 2.3 50 >100 0.3 0.5 0.09 Carcinoma HT-29 50 5.2 0.8 2.8 >50 2.1 94 1.9 4.5 0.05 HeLa 8.9 1.0 10 48.1 33 >10 >100 7.7 1.0 0.25 ACHN >5.0 3.1 1.2 41.5 15.5 >10 >100 3.0 3.0 0.44 5637 4.0 0.3 2.1 10 19 >10 18.9 0.7 2.7 0.02 Neuroblastoma IMR-32 5.8 0.6 ND ND 7.0 ND ND ND ND <0.01 a Compound concentration required to reduce cell multiplication by 50% under conditions allowing untreated controls to undergo at least three consecutive rounds of multiplication. L1210, mouse leukemia; Wil2-NS, human splenic B-lymphoblastoid cells; CCRF-SB, human acute B-lymphoblastoic leukemia; Raij, human Burkitt lymphoma; CCRF-CEM and MOLT-4, human acute T-lymphobastic leukemia; MT-4, human CD4+ T-cells containing an integrated HTLV-1 genome; HT-29, human colon adenocarcinoma; HeLa, human cervix carcinoma; ACHN, human renal adenocarcinoma; 5637, human bladder carcinoma; IMR-32, human neuroblastoma. ND: not determined. Full-size table Table options View in workspace Download as CSV Table 3. Antifungal activity of indolo[3,2-c]cinnolines MIC [μM]a Species 7a 7b 7c 7d 7e 7f 7g 7h 7i Miconazole C. albicans 150 9.4 12 >200 >200 >200 >200 1.6 66 7.5 C. parapsilosis 1.8 2.3 100 >200 >200 >200 >200 1.6 22 0.9 C. paratropicalis 37 19 50 >200 >200 >200 >200 1.6 66 7.5 C. neoformans 0.8 0.1 6.2 >200 >200 >200 >200 1.6 7.4 0.9 T. mentagrophytes 1.8 75 ND ND >200 ND ND ND ND 0.9 A. fumigatus 5.0 4.7 200 >200 >200 >200 >200 3.1 200 1.9 a Minimum inhibitory concentration. ND: not determined. Full-size table Table options View in workspace Download as CSV Table 4. Antibacterial activity indolo[3,2c]cinnolines MIC [μM]a Species 7a 7b 7c 7d 7e 7f 7g 7h 7i Streptomycin Streptococcus 0.2 0.1 0.4 6.2 3.1 6.2 >200 0.05 0.3 2.1 Staphlyococcus 0.1 0.07 0.4 6.2 6.2 6.2 100 0.02 0.09 4.2 Salmonella >200 >200 >200 >200 >200 >200 >200 3.1 200 8.6 Shigella >200 >200 >200 >200 >200 >200 >200 1.6 66 2.1 a Minimum inhibitory concentration. Full-size table Table options View in workspace Download as CSV , all title compounds showed antibacterial activity against gram-positive bacteria, being up to 200 times more potent than the reference drug streptomycin. Some of the indolo[3,2-c]cinnolines were also endowed with good antifungal activity, particularly against Cryptococcus neoformans.