4-Methyl-7-(tetradecanoyl)-2H-1-benzopyran-2-one: a novel DNA topoisomerase II inhibitor with adulticidal and embryostatic activity against sub-periodic Brugia malayi

Abstract

A compound of the coumarin class, 4-methyl-7-(tetradecanoyl)-2H-1-benzopyran-2-one, was evaluated for antifilarial activity against the human filarial parasite, Brugia malayi (sub-periodic strain) in Mastomys coucha. The test compound brought about a 24.4% reduction in circulating microfilaremia on day 8 after initiation of treatment when administered by the peritoneal route at a dose of 50 mg/kg for 5 consecutive days. The compound also caused a 62.0% mortality in adult parasites. Apart from killing adult filariids, it also brought about sterilization of 81.8% of the surviving female B. malayi. An oral dose of 200 mg/kg for 5 consecutive days was less effective (35.5% adulticidal efficacy and 65.8% sterilization). In vitro, the compound killed adult B. malayi at 100 microM concentration and inhibited DNA topoisomerase II activity in the filarial parasite. Studies are in progress using the compound in combination with standard antifilarials as well as other active agents.

Molecular Characterization of an rsmD -Like rRNA Methyltransferase from the Wolbachia Endosymbiont of Brugia malayi and Antifilarial Activity of Specific Inhibitors of the Enzyme

“…At the end of the observation period (on day 42), the treated and control jirds were euthanized and worms were recovered from the peritoneal cavity after vigorous washing and observed for their numbers, motility, death, or encapsulation, if any. All the surviving females were teased individually in a drop of PBS (pH 7.2) to examine the condition of the intrauterine contents (43). Any abnormality or death/distortion detected in the uterine stages, including oocytes, eggs, embryos, or mf, was considered an embryostatic/sterilization effect of the compound on the female worm, and the percentage of sterile females was assessed (42).…”

“…A group of mastomys was administered DEC (the standard filaricide) at 50 mg/kg for 7 days by the oral route. The microfilaricidal as well as adulticidal (macrofilaricidal) activities of the inhibitors were evaluated as described previously (43). Thick smears of 10 l tail blood were made from the treated and untreated animal groups just before the start of treatment, i.e., on day 0, and on day 15 after the initiation of treatment and thereafter continued at fixed intervals until day 90.…”

“…Microfilaricidal activity was assessed by the percent change in mf density from the pretreatment (day 0) level at each time point. At the end of the observation period (on day 90), the treated and control mastomys were euthanized and various tissues (lungs, heart, testes, lymph nodes) were isolated and teased gently in PBS to recover the adult parasites, which were subsequently examined to assess macrofilaricidal and embryostatic effects (43).…”

Search for new prototypes for the chemotherapy of filariasis: a chemotherapeutic and biochemical approach

“…The reported reduction in pathological swelling of human filarial patients by a combination of benzopyran-2-one (coumarin) and DEC (Casley-Smith et al 1993) led to the synthesis of a number of coumarin derivatives at our institute. Our earlier publications also revealed the adulticidal (macrofilaricidal) efficacy of few of these benzopyrone derivatives against the rodent filariids Acanthocheilonema viteae and Litomosoides carinii (Tripathi et al 2000), as well as the human filariid B. malayi Katiyar et al 2003;Misra-Bhattacharya et al 2004). These compounds also possessed filarial DNA topoisomerase II inhibiting properties (Tripathi et al 2000.…”

“…They play a crucial role in the organization of DNA within the cell nucleus as well as its structure and function. We have reported on filarial parasite DNA topoisomerase II as a target for the development of antifilarial agents (Katiyar et al 2003;Misra-Bhattacharya et al 2004). The reported reduction in pathological swelling of human filarial patients by a combination of benzopyran-2-one (coumarin) and DEC (Casley-Smith et al 1993) led to the synthesis of a number of coumarin derivatives at our institute.…”