The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.
A family of new fluorescently labeled ligands, HRDATI, was prepared to develop transition-metal-based NO sensing strategies. The ligands are composed of aminotroponiminates (ATIs) with a dansyl fluorophore on one of the imine nitrogen atoms and an alkyl substituent, either i-Pr (8), t-Bu (9), or Bz (10), on the other. Bis(chelate) Co2+ ([Co(i-PrDATI)2] (12), [Co(t-BuDATI)2] (14), [Co(BzDATI)2] (15)) and Zn2+ ([Zn(i-PrDATI)2] (13)) complexes were prepared and characterized by X-ray crystallography. The bis(ATI) complex [Co(i-Pr2ATI)2] (11) was also prepared and its X-ray crystal structure determined. Cyclic voltammetry reveals reversible redox waves at -2.57 and -0.045 V (vs Cp2Fe/Cp2Fe+) in THF for the Co2+/Co+ and Co3+/Co2+ couples, respectively, of 11. Only a Co2+/Co+ wave at -2.09 V is observed for 12. When excited at 350 nm, the HRDATI ligands and the diamagnetic Zn2+ complex 13 fluoresce around 500 nm, whereas the paramagnetic Co2+ complexes quench the fluorescence. These air-stable cobalt compounds react with nitric oxide to dissociate a DATI ligand and form neutral dinitrosyl complexes, [Co(NO)2(RDATI)]. The release of the fluorophore-containing ligand is accompanied by an increase in fluorescence intensity, thus providing a strategy for fluorescent NO sensing. Linking two DATI moieties via a tetramethylene chain affords the ligand H2DATI-4 (18). The Co2+ complex [Co(DATI-4)] (19) reacts more readily with NO than the bis(DATI) compounds and also displays an increase in fluorescence intensity upon NO binding.
Nitric oxide reacts selectively with the O2 stable, weakly fluorescent complex [Co(DATI‐4)] in dichloromethane solution to dissociate a fluorophore‐substituted arm of the aminotroponiminate ligand DATI‐4. The resulting cobalt–dinitrosyl adduct (see picture) effects a positive fluorescence response. The detection limit of 2 is 50–100 μM for NO.
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