Hydroxybenzothiazoles as New Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1)

17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC50-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics

In vitro anti-HIV and antitumor activity of new 3,6-disubstituted[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and Thiadiazine analogues

A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (7-15) and the thiadiazine analogues 16-18 have been synthesized under microwave irradiation (MWI). All synthesized compounds are evaluated for their antiviral activity against the replication of HIV-1 and HIV-2 activity in MT-4. However, compounds 12 and 18 showed EC(50) = 2.11 and 1.97 mug/mL. The results suggest that these compounds can be considered as a new lead in the development of antiviral agents. Compounds 4-18 were tested in vitro against a panel of tumor cell lines. All compounds are inactive against all the tumor sub-lines, except 10 which exhibited activity against CD4(+) human acute T-lymphoblastic leukaemia of CC(50) = 64 muM

Synthesis, in vitro antiproliferative and anti-HIV activity of new derivatives of 2-Piperazino-1,3-benzo[d]thiazoles

A series of N-{2-oxo-2-[4-(1,3-benzothiazol-2-yl)piperazin-1-yl]}-(het) arenecarboxamides 4a - l, sulfonamide derivatives 8a - i as well as benzothiazole-containing N 1-(2-oxoethyl)-N 1-arylthioureas 9a - c have been synthesized. Compounds 4a - l and 9a were evaluated, in vitro, for their antiproliferative activity against a large panel of human tumor-derived cell lines. Compounds 4l and 9a were the most potent analogs in this series, showing remarkable effects on human splenic B-lymphoblastoid cells (WIL-2NS) and human acute B-lymphoblastic leukemia (CCRF-SB) cell lines (4l: CC 50 = 5.1 and 7.3 μM, respectively), and compound 5 against CCRF-SB cell lines with CC 50 = 2.3 μM. These compounds are leading candidates for further development. Compounds 6 - 7a - i were screened as inhibitors against HIV-1 and HIV-2, and no activity has been witnessed

Synthesis and in vitro antiproliferative activity of new benzothiazole derivatives

A series of benzothiazole bearing piperazino-arylsulfonamides (5a-k), and arylthiol analogues (6a-j) as well as substituted benzothiazoles having sulfonamides (9b, 9l-n and 10) have been synthesized. All compounds were evaluated, in vitro, for their antiproliferative activity against a large panel of human tumor-derived cell lines. Compounds 5c, 5d, 5j, 6b, 6c and 6j were the most potent analogues in this series, showing activity against both cell lines derived from haematological and solid tumors (CC50 range = 8-24 μM), only 5d was found to be selective and not cytotoxic to normal human tissues