Search for new prototypes for the chemotherapy of filariasis: a chemotherapeutic and biochemical approach.
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.
Bajpai
Preeti
P
Division of Parasitology, Central Drug Research Institute, Post Box 173, 226001, Lucknow, Uttar Pradesh, India.
Verma
Shailendra Kumar
SK
Katiyar
Diksha
D
Tewari
Neetu
N
Tripathi
R P
RP
Bansal
Iti
I
Saxena
J K
JK
Misra-Bhattacharya
Shailja
S
D000588:Amines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D017178:Brugia malayi / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005368:Filariasis / Q000188:drug therapy* / Q000469:parasitology; D005369:Filaricides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D009115:Muridae; D021261:Parasitic Sensitivity Tests / Q000379:methods; D012376:Rodent Diseases / Q000188:drug therapy / Q000469:parasitology; D059005:Topoisomerase II Inhibitors
C486986:4-methyl-7-(tetradecanoyl)-2H-1-benzopyran-2-one; D000588:Amines; D000871:Anthelmintics; D003374:Coumarins; D004791:Enzyme Inhibitors; D005369:Filaricides; D059005:Topoisomerase II Inhibitors; D005947:Glucose
Indian J Med Res. 1984 Jun;79:749-54
6394476
Biochem Soc Trans. 1999 Aug;27(4):471-4
10917623
Arzneimittelforschung. 2003;53(12 ):857-63
14732967
Parasitol Res. 2004 Feb;92(3):177-82
14652743
Biochemistry. 2001 Mar 13;40(10):3009-15
11258914
Dev Biol. 1997 Dec 1;192(1):125-35
9405102
Eur J Med Chem. 2002 Sep;37(9):773-81
12350294
Acta Trop. 1998 Jul 30;70(3):251-5
9777711
Indian J Exp Biol. 1997 Jan;35(1):73-6
9279136
Acta Trop. 2003 Jul;87(2):193-205
12826295
Acta Trop. 2000 Sep 18;76(2):101-6
10936568
Blood. 1996 Nov 1;88(9):3259-87
8896391