Synthesis and Antileishmanial Activities of Some New Azasterols

A series of novel azasterols 8a―8h and 10a―10c were synthesized from the key intermediate 6 by acylation and deprotection.Compound 6 was obtained through a series of reactions including Wittig reaction,etherification,ene reaction,oxidation,oximation and reduction.Structures of the synthesized compounds were confirmed by IR,MS and 1H NMR.Furthermore,all of these compounds were screened for in vitro antiparasitic activity against L.donovani.Among them,compounds 8h,10a and 10b showed a fair inhibition of leishmania promastigotes growth at 25 μg/mL,with potencies close to that of the reference drug,amphotericin B.The results provide a starting point for the development of novel drugs to treat leishmaniasis.

Expeditious synthesis,antileishmanial and antioxidant activities of novel 3-substituted-4-hydroxycoumarin derivatives

A series of novel 3-substituted-4-hydroxycoumarin derivatives 6（a-1） were synthesized in high yield using one-pot three component coupling reaction catalyzed by ceric ammonium nitrate. These compounds were evaluated for antileishmanial activity against Leishmania donovani promastigotes and antioxidant activity（DPPH-radical scavenging activity）. Two compounds, 6h（IC50= 9.90 μmol/L） and 6i（IC50= 6.90 μmol/L） displayed potent antileishmanial activity when compared with standard antileishmanial agents pentamidine（IC50= 16.15 μmol/L） and miltefosine（IC50= 12.50 μmol/L）. Three compounds, 6c（IC50= 10.79 μmol/L）, 6h（IC50= 10.60 μmol/L）, and 6i（IC50= 10.73 μmol/L） showed significant antioxidant activity favorably with the antioxidant standards butylated hydroxy toluene（IC50= 16.47 μmol/L） and ascorbic acid（IC50= 12.69 μmol/L）. A molecular docking study of compounds 6（a-1） suggested a possible mode of binding with the Adenine phosphoribosyltransferase enzyme of L.donovani. ADME properties were predicted in silico and support the potential of 6（a-1） to show favorable drug-like properties.

Antimicrobial activity and DNA-fragmentation effect of isoflavonoids isolated from seeds of Millettia ferruginea,an endemic legume tree in Ethiopia

Objective:To investigate the seeds of Millettia ferruginea(M.ferruginea)to unravel its antibacterial,antifungal,antitubercular,and antileishmanial potential for the first time.Methods:M.ferruginea seeds were refluxed separately with chloroform,methanol and water to prepare the three extracts,which were tested against the reference strains of Gram-positive and Gram-negative bacteria,yeast cells,Mycobacterium tuberculosis and Leishmania donovani(L.donovani)promastigotes.Next,the seeds were chemically analysed to isolate three constituent compounds,viz.,barbigerone,calopogonium isoflavone-A and durmillone,which were purified,characterised and evaluated for antibacterial and antileishmanial activity.Further,Comet assay was conducted to observe DNA fragmentation effects on human peripheral blood mononuclear cells pretreated with the isoflavonoid compounds.Results:The chloroform and methanol extracts of M.ferruginea seeds exhibited antibacterial and antileishmanial activity.The pure compounds also showed inhibitory activity against Gram-negative ATCC strains(minimum inhibitory concentration~0.5μmol/L),and L.donovani promastigotes(IC_(50)8.2-87.3μg/mL).However,they had little or no activity against yeast cells and tubercle bacilli.The DNA fragmentation study showed that the isoflavonoid constituents of M.ferruginea seeds were safe at therapeutic doses.Conclusions:The antibacterial efficacy of the non-aqueous extracts of M.ferruginea seed was observed against both Gram-positive and Gram-negative ATCC strains.Moreover,the constituents isoflavonoids,viz.,barbigerone,calopogonium isoflavone-A and durmillone,exhibited inhibitory activity against Gram-negative ATCC strains and L.donovani promastigotes.The comet assay showed that the compounds were safe to be considered for human consumption.

Antileishmanial potential of a marine sponge Haliclona oculata against experimental visceral leishmaniasis

Objective:To evaluate the antileishmanial activity of a marine spongeHaliclona oculata.Methods:The crude methanol extract was prepared from the freshly collected sponge and its three fractions were also prepared by maceration method.The antileishmanial activity of these extract and fractions was tested againstLeishmania donovani.Results:The antileishmanial activity was tested bothin vitroand in vivo.The crude methanol extract exerted almost complete inhibition of promastigotes(81.0%±6.9%)and 78.8%±5.2%inhibition of intracellular amastigotes at 100μg/mL with IC_(50)values of 29.5μg/mL and 40.6μg/mL,respectively.The treatment of 500 mg/kg(p.o.)of the crude methanol extract for 5 d for Leishmania donovani infected hamsters resulted in 78.35%±10.20%inhibition of intracellular amastigotes.At a lower dose(250 mg/kg),it exhibited poor efficacy.Among the fractions,highestin vitro(>75%)and in vivo(84.3%±10.2%)antileishmanial activity was observed in n-chloroform fraction with IC_(50)values of 54.2μg/mL and 61μg/mL against promastigotes and intracellular amastigotes,respectively.Hexane fraction andn-butanol(both insoluble and soluble)fractions were found inactivein vitroand in vivo.Conclusions:Our findings indicate that this marine sponge has the potential to provide new insight toward development of an effective antileishmanial agent and,hence,more exhaustive studies are needed for exploiting the vast marine resources of the world to combat the scourge of several parasitic diseases.