The synthesis and antigiardial activity of formononetin analogues is hereby reported. Formononetin, an isoflavone commonly obtained from the Leguminoseae family has previously been reported to possess antigiardial activity. In this paper, 10 analogues of formononetin were synthesized and tested for antigiardial activity. One compound was found to be active, 3 were moderately active and 6 were found to be inactive. All the 10 analogues were found to be inactive against other protozoa such as Trichomonas vaginalis and Tritrichomonas foetus.Keywords: Antigiardial, Formononetin, Activit

Mutai, P

Rigo, G.V.

Tasca, T

English

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22  East and Central African Journal of Pharmaceutical Sciences  Vol. 19 (2016) 22-27 *Author to whom correspondence may be addressed. Email: tiana.tasca@ufrgs.br Synthesis and antigiardial activity of formononetin analogues  P. MUTAI1, G.V. RIGO2, T. TASCA2*  1Department of Pharmacology & Pharmacognosy, College of Health Sciences, University of Nairobi, PO Box 19676-00202, Nairobi Kenya 2Pharmacy Faculty, Federal University of Rio Grande do Sul, Avenida Ipiranga, 2752. 90610-000. Porto Alegre, RS, Brazil.  The synthesis and antigiardial activity of formononetin analogues is hereby reported. Formononetin, an isoflavone commonly obtained from the Leguminoseae family has previously been reported to possess antigiardial activity. In this paper, 10 analogues of formononetin were synthesized and tested for antigiardial activity. One compound was found to be active, 3 were moderately active and 6 were found to be inactive. All the 10 analogues were found to be inactive against other protozoa such as Trichomonas vaginalis and Tritrichomonas foetus.   Keywords Antigiardial, Formononetin, Activity  INTRODUCTION  Protozoal infections are a major global problem causing long term disability and death, with severe medical and psychological consequences around the world. Giardiasis, caused by Giardia lamblia (syn. Giardia intestinalis, Giardia duodenalis), is estimated to affect up to 33% of the population in developing countries [1]. Other reports indicate that the prevalence of human giardiasis in developing countries is about 20% and in some cases up to 43% while the prevalence in developed countries is about 5% [2]. Giardiasis is characterized by diarrheal disease and malabsorption syndrome in the severe cases. The infection is the most common cause of waterborne outbreaks of diarrhea in the United States and is occasionally seen as a cause of food-borne diarrhea [3]. The treatment of giardiasis has involved the use of nitroimidazoles such as metronidazole, benzimidazoles such as albendazole, nitazoxanide, paromomycin, furazolidine and quinacrine (Figure 1) [4-7]. Resistance against the drug of choice, metronidazole, has been reported [1,7]. There is therefore a need to search for new drug molecules for the management of giardiasis.   Formononetin is an isoflavone that is widespread in the Leguminoseae family. It has previously been reported to possess various pharmacological activities such as the inhibition of proliferation of prostate, breast   and colon cancer cells, wound and bone fracture healing, antihypertensive activity as well as anti-infective activities especially against giardiasis where it is reported to be more potent than metronidazole, the drug of choice in the treatment of giardiasis [8-11]. The mechanism of action for antigiardial activity has been proposed to be rapid detachment of trophozoites [12]. The antigiardial activity of the naturally occurring analogues of formononetin such as daidzein has been reported, but there is a need to report on the activity of synthetic analogues. This paper reports the synthesis and antigiardial activity of formononetin analogues.   EXPERIMENTAL  Synthesis of formononetin analogues was carried out by modification of rings A and B as well as the benzopyranone linker. Modifications on the benzopyrone linker were achieved through various synthetic schemes (Scheme 1) to yield 2 compounds 1 (PCK03) and 2 (PCK05)). Modifications on ring A and ring B were achieved through similar synthetic schemes. For ring A modifications, the starting materials had varied substituents at either position 5 or 6 while for ring B modifications, the scheme started with protection of the para-hydroxyl group on ring A (Scheme 2) to yield compounds 3 to 8 (PCK33C, PCK36B, PCK39B, PCK43B, PCK44E and PCK46C). Compounds 9 (PMK01) and 10 (PMK02) were obtained commercially. 23 Mutai et al. East Cent. Afr. J. Pharm. Sci. 19 (2016)  Figure 1. Examples of antigiardial compounds of clinical significance.   Scheme 1: Reagents and conditions: (i) N2H4.H2O; EtOH, reflux, 60-80°C, 2h (ii) Hydroxylamine hydrochloride, N-methylmorpholine, EtOH, Reflux, 80°C, 8h 24 Mutai et al. East Cent. Afr. J. Pharm. Sci. 19 (2016)   Scheme 2: Reagents and conditions: (i) DMF-DMA, 95°C, 3h (ii) I2, pyridine, CHCl3, rt, 12h, (iii) ArB(OH)2, Pd/C, Na2CO3, DME/H2O, 45°C, 4h (iv) DHP, PPTS, DCM, rt, 4h (v) p-TsOH, MeOH, THF, 60°C, 2h  For antiprotozoal activity, the isolate 30236 of T. vaginalis from American Type Culture Collection (ATCC) and the isolate TFK of T. foetus isolated by Dr. H. Guida (Embrapa, Rio de Janeiro, Brazil) from the urogenital tract of a bull were used. The isolate WB of G. lamblia kindly donated by Dr. Adriana Lanfredi Rangel (FIOCRUZ, Bahia, Brazil) was used. The results were qualitatively expressed considering viable trophozoites (normal morphology and motility) compared to untreated parasites [13, 14]. Compounds that revealed potential activity against G. lamblia in the screening assay were tested in the quantitative assay.  RESULTS  All the compounds tested were inactive against T. vaginalis and T. foetus. This corroborates well with previously reported data where formononetin was found to be inactive against other protozoa tested [11,12]. Four compounds exhibited some antigiardial activity (Table 1).   The compound PMK02 presented the highest activity against G. lamblia trophozoites at 1.0 µM (Figure 2). As expected, the positive control metronidazole (100 µM) reduced 100% of parasite viability (data not shown).   ACKNOWLEDGEMENTS  P.M. is grateful to the USHEPiA Programme, South Africa for funding this work. This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil (grant 474930/2012-2) to T.T. G.V.R. receives scholarship from Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (PROBIC/FAPERGS/UFRGS), Brazil and Tiana Tasca is supported by a research fellowship from CNPq.      25 Mutai et al. East Cent. Afr. J. Pharm. Sci. 19 (2016)  Table 1: Antiprotozoal activity of formononetin analogues   MW STRUCTURE Solubility T. vaginalis T. foetus G. lamblia PCK03  282.29  >200 Inactive Inactive Inactive PCK05 283.28  >200 Inactive Inactive Moderately active PCK33C 222.24  80 Inactive Inactive Active  PCK36B  263.25  80 Inactive Inactive Moderately active PCK39B 286.25  40 Inactive Inactive Inactive  PCK43B  298.29  80 Inactive Inactive Inactive  PCK44E  268.26  20-40 Inactive Inactive Moderately active  PCK46C  286.71  10-20 Inactive Inactive Inactive  PMK01  270.24  40 Inactive Inactive Inactive  PMK02  254.24  20-40 Inactive Inactive Active 26 Mutai et al. East Cent. Afr. J. Pharm. Sci. 19 (2016)   Figure 2. Antigiardial activity of four analogues of formononetin.  Control means only trophozoites in TYM medium (without compounds), and vehicle means control for solubilization with 0.6% DMSO. Bars represent the mean ± SD of four different experiments (parasite suspensions), all in triplicate.  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Synthesis and antigiardial activity of formononetin analogues

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Synthesis and antigiardial activity of formononetin analogues

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