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Emergence of drug-resistant Plasmodium falciparum strains has led to a situation of haste in the scientific and pharmaceutical communities. Hence, all their efforts are redirected toward finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. In light of this situation, scientists have come up with the concept of hybridization of two or more active pharmacophores into a single chemical entity, resulting in "antimalarial hybrids." The approach has been applied widely for generation of lead compounds against deadly diseases such as cancer and AIDS, with a proven potential for use as novel drugs, but is comparatively new in the sphere of antimalarial drug discovery. A sudden surge has been evidenced in the number of studies on the design and synthesis of hybrids for treating malaria and may be regarded as proof of their potential advantages over artemisinin-based combination therapy (ACT). However, it is evident from recent studies that most of the potential advantages of antimalarial hybrids, such as lower toxicity, better pharmacokinetics, and easier formulation, have yet to be realized. A number of questions left unaddressed at present need to be answered before this approach can progress to the late stages of clinical development and prove their worth in the clinic. To the best of our knowledge, this compilation is the first attempt to shed light on the shortcomings that are surfacing as more and more studies on molecular hybridization of the active pharmacophores of known antimalarials are being published.

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Malaria still remains a global health problem despite of the availability of effective control and treatment measures. In the present study, a novel series of [1, 2,3]‐triazole tethered sulfonamide‐berberine hybrids were synthesized in good yields via Huisgen [3+2] cycloaddition reaction of various primary, secondary and tertiary sulfonamide based azides with 9‐O‐(propyne)berberine chloride in t‐BuOH:water (1:1) mixture containing a catalytic amount of sodium ascorbate and CuSO4.5H2O at 90oC. After spectroscopic characterization, these novel hybrids were evaluated for their potency against asexual erythrocytic stages of P. falciparum (3D7) in vitro. Most of the synthesized compounds have shown significant antimalarial activity with IC50 values in the range of 0.1‐20 μg/mL and were also found to be non‐cytotoxic under tested conditions.

BackgroundEmergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT).MethodsFluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters’ four-day suppressive test.ResultsPromising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW).ConclusionsIn vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.