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

Abstract

The antifilarial activity of two coumarin derivatives (A, B) and three glycosyl amine derivatives (D, E, F) was evaluated against a subperiodic strain of human lymphatic filarial parasite Brugia malayi by the intraperitoneal route at 50 mg/kg for 5 consecutive days. Of these, the two sugar derivatives (D and E) were selected for evaluation by the oral route based on their microfilaricidal (mild), macrofilaricidal and female worm sterilization efficacy using the i.p. route of administration. Compound E was finally selected for combination therapy on the basis of its microfilaricidal and embryostatic action by the oral route and its spectrum of activity against micro- and macrofilariae including embryostatic activity by the i.p. route. In addition, E also significantly inhibited the parasite DNA topoisomerase II. Compound A, in contrast, led to an enhanced adult worm burden. Compound B was toxic by the i.p. route, killing all of the treated animals before completion of the experiment. Some of these compounds demonstrated significant antifilarial efficacy of varying degree when tested in vitro Compounds B, D and F also killed adult B. malayi in vitro at 100 muM while 50 muM resulted in very slow motility of worms. Compound E in combination with a promising macrofilaricidal benzopyran derivative reported by us recently (compound C) did not show any synergistic or additive effect. These two compounds (C and E) individually on oral administration with either DEC or ivermectin significantly improved microfilaricidal efficacy in terms of intensity and duration of suppressed microfilaraemia. The combination of DEC with compound E demonstrated marginal enhancement in adulticidal efficacy, however, the embryostatic effect of the duo was significantly higher than that exerted by the individual agents. It may thus be inferred that in the absence of an adulticidal antifilarial drug, the use of potential antifilarials in combination with the standard filaricides may yield better results.

Antifilarial Activity of Eucalyptus globulus Labill. Leaves Against Brugia malayi

“…Dunnett's multiple (Bajpai et al, 2005) comparison test was applied to assess the statistical significance of the values between treated and control group. Values were expressed as mean ± SE.…”

“…The recovered parasites were counted and examined for motility, death or calcification. Live female worms were teased in a drop of phosphate buffer saline (PBS, pH 7.2) to dissect out the uterus for observing the uterine contents microscopically to assess the embryostatic effect of test samples, if any (Bajpai et al, 2005). The peritoneal washing collected on autopsy was microscopically observed to assess the effect of test sample on released microfilariae.…”

A novel filarial topoisomerase II inhibitor produced by native isolate Micrococcus luteus B1252

“…A suitable, safe and effective filaricide would allow more impact to be made on controlling filarial diseases. Filarial parasite DNA topo II is a major target for the development of antifilarial agents (Katiyar et al, 2003;Misra-Bhattacharya et al, 2004;Bajpai et al, 2005;Prabhakaran et al, 2011). This investigation deals with the anti topo II activity of the microorganism Micrococcus luteus BI252 to target filarial infection.…”

In vitro antifilarial activity of glutathione S-transferase inhibitors

“…In spite of the valuable additions to our knowledge on newer molecules (Lazdins and Kron 1999;Tewari et al 2000) with antifilarial activity, none has come out successfully as a macrofilaricidal drug due to their low antifilarial activity or high toxicity. Since effective treatment for the adult worms is currently unavailable, new chemical classes of compounds with macrofilaricidal activity are now required (Bajpai et al 2005).…”