Pak. J. Pharm. Sci., Vol.27, No.6, November 2014, pp.1767-1773 1767 Evaluation of some 1H-pyrazole derivatives as a dual acting antimalarial and anti-leishmanial agents Adnan Ahmed Bekhit 1,2* , Tizita Haimanot 1 and Ariaya Hymete 1 1 Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Abstract: The synthesis of a novel series of 1H-pyrazole derivatives was achieved by condensation of pyrazole aldehyde 1 with hydrazine hydrate to give hydrazone 7. On the other hand, cyclization of α,β-unsaturated ketone counterpart 2 using hydrazine hydrate in liquid aliphatic acids rendered compounds 4-6 and hydrazine hydrate in ethanol afforded compound 3. The later was allowed to react with aroyl chloride giving rise to compounds 8, 9. All compounds were tested for their in vivo anti-malarial and in vitro antileishmanial activities. The anti-malarial activity was performed using Plasmodium berghei infected mice, while the anti-leishmanial activity of the compounds was determined against Leishmania aethiopica promastigotes using alamar blue reduction assay. Compound 3, 1-(4-methylphenyl)-3-phenyl-4- [3-(2-thienyl)-2-pyrazolin-5-yl]-1H-pyrazole, possessed the highest anti-malarial activity with suppression of 70.26%. The highest anti-leishmanial activity was exhibited by compound 2, 1-(4-methylphenyl)-3-phenyl-4-[1-(2-thienyl)-prop- 2-en-1-one]-1H-pyrazole, with an IC 50 of 0.079µg/ml. Hydrazone 7 showed appreciable dual anti-malarial (suppression = 62.30%) and anti-leishmanial activity (IC 50 = 1.823µg/ml). Keywords: 1H-pyrazole, plasmodium berghei, anti-malarial activity, alamar blue, leishmania aethiopica, anti- leishmanial activity, acute toxicity INTRODUCTION Malaria is a parasitic infection that has drastic effects on human worldwide. According to WHO malaria report, 243 million cases of malaria were estimated worldwide. The preponderance of infection cases (85%) are found in Africa. This disease resulted in about 863, 000 death cases in 2008 with approximately 89% were in African countries (WHO, 2009). Malaria is a protozoan disease, which is caused by parasites of the genus Plasmodium and transmitted to man by the sting of certain species of infected female anopheline mosquito. Four types of Plasmodium species commonly encountered in human infection: P. falciparum, P. vivax, P. malariae and P. ovale. Among these, P. falciparum and P. vivax are frequently found to cause the illness. However, the majority of severe disease and death has been recorded due to P. falciparum (Kalra et al., 2006). The condition is getting worse primarily due to the absence of effective drugs and development of drug resistance. Quinoline derivatives, anti-folates and artemisinins have been the mainstays for treatment of malaria (Valderramos and Fidock, 2006). Leishmaniasis is worldwide distributed with major infection regions being Southern Europe, North and East Africa, Central and South America, the Middle East, and the Indian subcontinent (Habtemariam, 2003). It is caused by obligate intracellular vector-borne parasites, which belong to genus Leishmania and family Trypanosomatidae. The parasites are transferred to humans by an insect vector, phlebotomine sand flies, through bite attacks. There are three clinical types of leishmaniasis, visceral leishmaniasis, cutaneous leishmaniasis and mucocutaneous leishmaniasis. Sodium stibogluconate, amphotericin B, miltefosine, pentamidine and paramomycin are drugs used for treatment of leishmaniasis (Croft et al., 2006) Resistance was reported to all currently existing anti-malarial and anti-leishmanial drugs, in addition to their toxicity. To tackle this problem new agents are urgently needed. It has been reported that several pyrazole derivatives showed anti-malarial (Acharya et al., 2010) and anti- leishmanial activity (Santos et al., 2011). We have already reported the anti-malarial activity of some pyrazole derivatives (Bekhit et al., 2012). This work presents our attempt to design and synthesize novel pyrazole derivatives with selected substitution pattern to study the effect of such molecular variation on the anti- malarial and anti-leishmanial activities. MATERIALS AND METHODS Chemistry The compounds were synthesized according to the scheme shown in fig. 1. The determinations of melting points were performed in open glass capillaries using electro thermal BUCHI (B-540) hot storage melting-point apparatus and are uncorrected. Infra-red (IR) spectra was recorded on Shimadzu 8400SP infrared spectro- photometer using nujol and KBr. 1 H NMR spectra was recorded on Bruker Avance DMX400 400MHz FT-NMR *Corresponding author: e-mail: adnbekhit@hotmail.com