Antifilarial activity

Several transition-metal complexes were evaluated for their in vitro antifilarial activity, with... 

Rao, U.R., Mehta, K., Subrahmanyam, D. and Vickery, A.C. (1991) Brugia malayi and Acanthocheilonema viteae- antifilarial activity of transglutaminase inhibitors in vitro. Antimicrobial Agents and Chemotherapy 35, 2219-2224. 

Denham, D.A., S.L. Oxenham, I. Midwinter, and E.A.H. Friedheim. 1986. The antifilarial activity of a novel group of organic arsenicals upon Brugia pahangi. Jour. Helminthol. 60 169-172. 

In general, the following in vivo models are used for screening of antifilarial activity of new compounds. 

In another approach, where the 2-methyl carbamate moiety was replaced by a more lipophilic group such as SC02R, SCONR R2 or S(CH2) C02R etc. [33] more soluble compounds were generated. Surprisingly, the resulting compounds exhibited a complete loss of antifilarial activity. It is evident from these studies that the carbamate moiety is an essential pharmacophore for antifilarial activity. 

Table 4.1. ANTIFILARIAL ACTIVITY OF MEBENDAZOLE, FLUBENDAZOLE AND NEW CLASS OF BENZIMIDAZOLE CARBAMATES...

A X Dosage (route) (mglkg) Antifilarial activity (% reduction of adult worms) B. pahangi L. carinii ... 

Goa KL, McTavish D, Clissold SP. Ivermectin. A review of its antifilarial activity, pharmacokinetic properties and clinical efficacy in onchocerciasis. Drugs 1991 42 640-658. 

Radembino, N. Loisau, P.M. Dessalles, M.-C. Marchat, L. Bories, C. Gayral, P. Mahuzier, G. Epoxyethane/ ethynesulfonamides with antifilarial activities. Arzneim. Forsch/Drug Res. 1998, 48, 294-299. 

Following the discovery of antileishmanial and antifilarial activities of tartar emetic [3], a number of organoantimonials were prepared as possible antiparasitic agents. 

Following the discovery of DEC, a series of 1,4-disubstituted piperazines (5) were synthesized, many of which showed moderate to good antifilarial activity. The noteworthy active analogues of DEC belonging to this class are 6 [13]. When tested against Litomosoides carinii infection in cotton rats, l-isobutoxycarbonyl-4-methylpiperazine (6) caused 91% reduction of microfilariae in blood at an intraperi-toneal dose of 3 mg/kg during 5 days and also killed 100% of the microfilariae and... 

A series of l-carbamoyl-4-methylpiperazines were prepared of which 1-meth-yl-4-(pyrrolidin-l-yl-carbonyl)piperazine (9) was found to exhibit excellent antifilarial activities. The compound caused more than 92% elimination of microfilariae of L. carinii and D. viteae in rodents at an oral dose of 3 and 12 mg/kg, respectively. It also showed higher therapeutic indices and lower LDjq values than DEC [17]. 

The fact that demethylation of DEC gives rise to inactive metabolites prompted Wise et al. [18] to synthesize some l-dialkyl-4-diethylcarbamoylpiperaz-inium salts (10) which would resist a DEC-like demethylation in znvo. A few piperazine-N-oxides (11) have also been prepared [19] however, none of these compounds exhibited antifilarial activity better than DEC. 

Most of the compounds represented by the molecular skeletons 16-22 either had little or no antifilarial activity except for 18, which was found to be half as active as DEC. The lack of desired antifilarial activity in 16-22 was explained on the basis of their molecular geometry. None of the above non-piperazine analogues represented the exact interatomic distances and molecular geometry as shown by DEC. This indicated that the interatomic distances between the nitrogen atoms and the spatial disposition of the functional groups in DEC are of importance in governing antifilarial activity. 

Brookes and coworkers [32] have studied the effect of replacement of the piperazine ring by other diacidic cyclic bases on antifilarial response. Consequently, a series of 2,4 -dipiperidyl, 4,4 -dipiperidyl and 4-aminopiperidines with a diethylcarbamoyl chain were prepared and evaluated for their antifilarial activity. The most effective compounds of this class were 23-26 possessing marked activity against the microfilariae of L. carinii, but none was better than DEC. 

Hoechst laboratories synthesized a large variety of 2-phenyl-5-substituted benzimidazoles of which HOE-33258 (32) was found to possess high micro- and macrofilaricidal activity against L. carinii in cotton rats at a subcutaneous dose of 4-8 mg/kg given for 5 days [37]. Despite the strong antifilarial activity exhibited by 32, it was not pursued further due to its strong binding with the hosTs DNA [38]. 

The marked anthelmintic activity associated with 5-aminobenzimidazoles like cambendazole (5), prompted the synthesis of various 5(6)-substituted aminobenzimi-dazole-2-carbamates (54). These, however, showed poor anthelmintic activity, except for the benzimidazoles (55), which carry a piperazin-l-yl residue at the 5-position [47,66,89-91]. Of these, the 5(6)-(4-substituted piperazin-l-yl)benzimidazoles (55) exhibited highly antifilarial activity, the most notable being the Hoechst compound HOE-33258 (32) and 55a,b. 

The antifilarial activity of suramin is attributed to its ability to inhibit regulatory en2ymes such as protein-kinase or DHFR in the parasites. Presumably it kills O. volvulus because the DHFR enzyme of the filariid is more sensitive than of the host [101]. 

Cardol (47), one of the phenolic lipids that characterise extracts of members of the plant family Anacardiaceae [118] showed pronounced antifilarial activity (LDioo 3.5 ppm) [119]. In rats, it was tolerated up to concentrations of 5 g/kg body weight. For activity, the phenolic hydroxyls and the alkyl side chain were necessary [119,120]. The related compound urushiol (48) showed toxicity to Ascaris suilla [121]. 

Ethyl-2-methyl-octahydropyrazino[l,2-c]pyrimidin-6(6//)-one (centperazine) (56) exhibits a very strong antifilarial activity. This compound has been undergoing Phase II clinical trials... 

Fig. 21. Structural and Variance Information (SVI) plot of in vitro antifilarial activity (-LOGEC50). The data set considered combines -LOGEC50 with the complete set of descriptors of the Selwood dataset.

Fig. 24. MEDA matrix of the PCA model with 10 PCs from the data set which combines the in vitro antifilarial activity (-LOGEC50) with the complete set of descriptors of the Selwood dataset. Two common factors are highlighted. The first one is mainly found in descriptors 1 to 3,5 to 7,17, 52 and 53. The second one is mainly foimd in descriptors 35,36,38 to 40,45,47 and 50. Though the second common factor is not present in -LOGEC50, it is in LOGP.

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