ABSTRACT
As a part of our program to develop new antifungal agents, a series of fluconazole analogues was designed and synthesized wherein one of the triazole moieties in fluconazole was replaced with 2H-1,4-benzothiazin-3(4H)-one or 2H-1,4-benzoxazin-3(4H)-one moiety. The new chemical entities thus synthesized were screened against various fungi and it was observed that the compounds 4a and 4i are potent inhibitors of Candida strains. The structure-activity relationship for these compounds is discussed.
Subject(s)
Antifungal Agents/chemistry , Benzothiazoles/chemistry , Benzoxazines/chemistry , Benzoxazoles/chemistry , Fluconazole/analogs & derivatives , Thiazines/chemistry , Antifungal Agents/pharmacology , Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Candida/drug effects , Fluconazole/chemical synthesis , Fluconazole/chemistry , Fluconazole/pharmacology , Microbial Sensitivity Tests , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/pharmacologyABSTRACT
A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Cyclopentanes/chemical synthesis , Stilbenes/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclopentanes/pharmacokinetics , Cyclopentanes/pharmacology , DNA Fragmentation , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Solubility , Stilbenes/pharmacokinetics , Stilbenes/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacologyABSTRACT
The enantiomers of 5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one, a novel anticancer agent, were separated by derivatisation with caronaldehyde, separation of the resulting diastereoisomers of the corresponding esters by silica gel column chromatography and regeneration of alcohols (S)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one and (R)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one under aqueous conditions. The absolute configuration of the enantiomers was determined by 1H NMR studies of the corresponding Mosher esters. Alternatively, the enantiomers were separated by preparative HPLC to collect the (S)- and (R)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-ones with high purity which was comparable with that obtained by the chemical method. The details of these methods have been presented herein.
Subject(s)
Antineoplastic Agents/chemistry , Chromatography, High Pressure Liquid/methods , Cyclopentanes/chemistry , Antineoplastic Agents/analysis , Cyclopentanes/analysis , Molecular Structure , StereoisomerismABSTRACT
The larvicidal activities of various fractions of the hexane extract of the seeds of Sterculia guttata against larvae of Aedes aegypti and Culex quinquefasciatus were determined. Bis(2-ethylhexyl) benzene-1,2-dicarboxylate (1) was identified as one of the active principles, displaying chronic toxicity against both types of larvae, with LD50 values of 79 and 64 ppm, respectively.
Subject(s)
Aedes/drug effects , Benzene/pharmacology , Culex/drug effects , Dicarboxylic Acids/pharmacology , Insecticides/pharmacology , Seeds , Sterculia , Aedes/physiology , Animals , Benzene/chemistry , Benzene/isolation & purification , Culex/physiology , Culicidae , Dicarboxylic Acids/chemistry , Dicarboxylic Acids/isolation & purification , Insecticides/chemistry , Insecticides/isolation & purification , Larva/drug effects , Larva/physiology , Mosquito Control/methods , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Species SpecificityABSTRACT
The larvicidal activity of ethanol, chloroform and hexane soxhlet extracts obtained from S. guttata seeds was investigated against the IVth instar larvae of Dengue fever vector, Aedes aegypti and filarial vector, Culex quinquefasciatus. All extracts including fractions of ethanol extract exhibited 100% larval kill within 24 hr exposure period at 500 ppm concentration. Fraction A1 of ethanol was found to be most promising; its LC50 was 21.552 and 35.520 ppm against C. quinquefasciatus and A. aegypti respectively. Naturally occurring S. guttata seed derived fractions merit further study as potential mosquito larval control agents or lead compounds.
