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Abstract: A series of 15-membered azalide urea and thiourea derivatives has been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (D6), chloroquine/pyremethamine resistant (W2) and multidrug resistant (TM91C235) strains of Plasmodium falciparum. We have developed an effective automated synthetic strategy for the rapid synthesis of urea/thiourea libraries of a macrolide scaffold. Compounds have been synthesized using a solution phase strategy with overall yields of 50–80%. Most of the synthesized compounds had inhibitory effects. The top 10 compounds were 30–65 times more potent than azithromycin, an azalide with antimalarial activity, against all three strains. [Copyright &y& Elsevier]

Abstract: Eleven new tetraoxanes possessing cholic acid-derived carrier and isopropylidene moiety were synthesized and were tested in vitro and in vivo. In vitro screening revealed that nine of them were more potent against CQ-resistant W2 than CQ-susceptible D6 strain and that two of them were equally or more potent than artemisinin and mefloquine against multi-drug resistant TM91C235 strain. Amine 8 cured all mice at the dose of 160mg/kg/day, while the anilide 9 exhibited MCD⩽20mg/kg/day. The diol 13 was most potent antiproliferative with GI50, TGI, LC50 MG_MID 0.98μM, 3.80μM, 11.22μM, respectively. All tested compounds showed no toxic effects. [Copyright &y& Elsevier]

Abstract: Tryprostatin A is an inhibitor of breast cancer resistance protein, consequently a series of structure–activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration l-Tyr-l-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole Na–H in 1 with various alkyl or aryl groups, incorporation of various l-amino acids into the diketopiperazine ring in place of l-proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole Na–H or the indole C-2 position influenced the mechanism of action of these analogues. Analogues 68 (IC50 =10μM) and 67 (IC50 =19μM) were 7-fold and 3.5-fold more potent, respectively, than 1 (IC50 =68μM) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC50 =11.9μM), MCF-7 (IC50 =17.0μM) and PC-3 (IC50 =11.1μM) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP. [Copyright &y& Elsevier]