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The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.

Five-membered heteroaromatic ring fused pyridine derivatives are of increasing interest in drug design and medicinal chemistry. The structural similarity of many drugs (especially antiviral and anticancer ones) with DNA bases such as adenine and guanine is a key factor to explain their effectiveness. Apart from these, it is also found in the structures of substances with antituberculosis, antibacterial, antifungal, anti-inflammatory, and antimalarial activities. Another advantage of this group of compounds is their positive contribution to solubility, polarity, lipophilicity, and hydrogen bonding capacity properties of the compounds they are incorporated into. In this chapter, various bioactivities of fused pyridine derivatives will be categorized and summarized.

WOS: 000361222900001, Majority of anti-cancer drugs were shown to exert their activities by interfering with DNA topoisomerase reactions. Since the identification of Camptothecin as the topoisomerase I targeting compound, these enzymes are widely utilized in biological assays to assess the pharmaceutical significance of the synthetic and natural agents. Because a considerable number of compounds were shown to have cytostatic activities via blocking topoisomerase reactions, we aimed to identify if the previously-reported physiological activities of acetonapthones involves the interference with topoisomerase reactions. We covered topoisomerase activity and cytostatic activity evaluation of piperidinopropionaphthone hydrochloride type Mannich base (MB) to compare its bioactivities to the starting propionaphtone in order to assess the contribution of aminomethyl moiety of the compound on its bioactivity. MB was synthesized and characterized in our laboratory. Supercoiled plasmid relaxation and decatenation assays were carried out to evaluate their biological activities in mammalian DNA topoisomerases. We also assayed the cytostatic activities using HeLa, MCF7 and A431 cell lines. Our data showed a considerable inhibition of MB on type I and type II DNA topoisomerases without a correlation to cytostatic assays. MB exerted a modest activity against the proliferation of MCF7 cells with an IC50 value of 27.62 mu M. The presence of MB inhibited topo II decatenation activity as well. Results offer no direct explanation for the contradictory effects on the DNA topoisomerases and the proliferation of cancer cells in vitro. Our results are discussed in relation to potential significance of aminomethyl group of Mannich base in the course of drug-development studies.

Mannich bases are pharmacologically important molecules having wide range of bioactivities. We previously synthesized and characterized a number of Mannich base derivatives of planar polycyclic/heterocyclic starting materials of which four of them [MB1 (3-(bis(2-chloroethyl)amino)-1-phenylpropan-1-one hydrochloride), MB2 (3-(bis(2-chloroethyl)amino)-1-(naphthalen-2-yl) propan-1-one hydrochloride), MB3 (3-(bis(2-chloroethyl)amino)-1-(phenanthren-3-yl)propan-1-one hydrochloride) and MB4(3-morpholino-1-(pyren-1-yl)propan-1-one hydrochloride)] manifested anti-proliferative effects in three cancer cell lines (PC3, HeLa, and MCF7) and one non-tumoral cell line (293 HEK). Because several reports covering anti-proliferation address DNA topoisomerases as the cellular targets, we undertook further assays using these four compounds with type I and type II topoisomerases to identify if their effects were mediated through topoisomerase reactions. Our results indicated that the three of these compounds (MB2, MB3 and MB4) target topoisomerase II without affecting type I topoisomerase. However, targeting type II enzyme did not generate considerable strand breaks, which in turn places the compounds MB2, MB3 and MB4 in potential topoisomerase II inhibitors, not poisons.