*2.4.7 Tryparedoxin peroxidase (TryPI, TXNPx, EC 1.11.1.15)*

Crystal structures of the tryparedoxin-tryparedoxin (TXN-TXNPx) peroxidase couple were reported but there is no study that targeted this system with antileishmanial activity [111].

*Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment DOI: http://dx.doi.org/10.5772/intechopen.101132*

### **2.5 Phosphotidylinositol-3-kinase (PI3K, EC 2.7.1.137)**

The discovery of apoptotic pathways regulated by intracellular protozoan parasites and inhibit apoptosis, studies on signaling pathways have accelerated [112–114]. Interestingly, it was reported that there is an *L. major* PI3K mediated negative feedback mechanism for IL-12 production and PI3K/Akt signaling in *Leishmania* promastigotes [115].

Various heterocyclic compounds (quinoline, quinazoline, purine, thiazolopyrimidine scaffolds, etc.) as PI3K inhibitors were reported for treatment of several diseases alongside *Leishmania* [116, 117]. Later, Khadem et al. showed idelalisib known PI3K inhibitor—and ampB combination therapy resulted in the reduction in parasite burden and moderate immune response [117]. A recent study showed that PI3K/mTOR inhibitor Torin2, Dactolisib, and NVP-BGT226 also possess good antileishmanial activity [118].

Imidazo[1,2-b]pyridazin scaffold was designed to inhibit various eukaryotic kinases by Bendjeddou et al. [119]. In this study, some of the compounds were tested against *L. amazonensis* parasites. The compounds showed antileishmanial activity at rather high concentrations (10 μM) although the compounds have not exhibited any toxicity at cell viability assays regarding concentrations [119].

Because of *Leishmania* parasite has a life cycle in the mammalian host, inhibition of signal transduction protein kinases for antileishmanial activities was investigated. Polyfluoroalkyl sp2 -glycolipid compounds were reported with antileishmanial properties by binding p38a-MAPK [120]. Purine derivatives, benzopyrroles, and benzopyrrolidines exhibited CRK3 cyclin-dependent kinase inhibitory properties and showed antileishmanial activity upon *Labrus donovani* amastigotes [121]. Lastly, a chemical inhibitor of heat shock protein 78 (HSP78), namely Ap5A reported with antileishmanial activity [122].

#### **2.6 Topoisomerase I and II (TOPI, EC 5.6.2.1; TOPII, EC 5.6.2.2)**

Topoisomerases are enzymes that modulate DNA topology. Firstly, topoisomerase II and then topoisomerase I enzymes were reported in *Leishmania* species [123, 124].

Different classes of TOP inhibitors show activity against *L. donovani* parasites by the means of DNA TOPI catalytic activity. The most important point is providing selectivity over parasite-human topoisomerase enzymes [125]. Pentostam's one of the proposed modes of action is inhibition of TOPI of *L. donovani* [126]. Werbovetz et al. tested known TOPII inhibitors, acridine derivatives, against *L. chagasi* and *L. donovani*, therefore, it was suggested that TOPII could serve as a useful target for parasite chemotherapy [127].

16-phenyl-6-hexadecynoic acid and 16-phenylhexadecanoic acid derivatives were synthesized by Carballeira et al. [128]. Compounds 1 and 2 showed promising activity on *L. donovani* TOPIB (EC50 14 μM and 36 μM, respectively). Moreover, compounds 1 and 2 showed cytotoxicity toward L. infantum amastigotes (IC50 of 3–6 μM) and L. infantum promastigotes (IC50 of 60–70 μM) [128].

In another study, compounds bearing 1,5-naphthyridine scaffold were reported [129]. Compound 22 was found to be one of the promising ones with the IC50 value (0.58 ± 0.03 μM) against L. infantum amastigotes similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and selectivity over host murine splenocytes. Additionally, this compound showed remarkable inhibition on leishmanial TopIB [129].

Three compounds were identified in a very recent virtual screening campaign with a significant *Ld*TopIB activity (IC50of LRL-TP-85: 1.3 μM; LRL-TP-94: 2.9 μM; and LRL-TP-101: 35.3 μM) [130]. Further studies showed that compounds were selective for *Ld*TopIB over *Homo sapiens* (Hs) TopIB. After that, compounds were evaluated for their in extracellular promastigote (4.9 μM, 1.4 μM, and 27.8 μM, respectively) and intracellular amastigote (34.0 μM, 53.7 μM, and 11.4 μM, respectively) activities [130].

Apart from these recent advances, several scaffolds such as bis-naphtoquinone [131, 132] betulinic acid derivatives [133], bisbenzimidazoles [134] and protoberberine alkaloids [135], and 1,3,4-thiadiazole derivatives [136] were identified with TOP inhibitor activity as potential antileishmanial compounds. Additionally, acetylenic fatty acids, 6-heptadecynoic acid, and 6-icosynoic acid derivatives [137], 2-octadecynoic acid [138], 3,3′-diindolylmethane derivatives [139], bis-lawsone analogs [140], spirooxindole derivatives [141], indeno-1,5-naphthyridines [142], diamidine derivatives [143], and copper salisylaldoxime [144] compounds are other reported topoisomerase inhibitors with antileishmanial activity.
