Discovery, SAR and mechanistic studies of quinazolinone-based acetamide derivatives in experimental visceral leishmaniasis.

Towards identification of novel therapeutic candidates, a series of quinazolinone-based acetamide derivatives were synthesized and assessed for their anti-leishmanial efficacy. Amongst synthesized derivatives, compounds F12, F27 and F30 demonstrated remarkable activity towards intracellular L. donovani amastigotes in vitro, with IC50 values of 5.76 ± 0.84 µM, 3.39 ± 0.85 µM and 8.26 ± 1.23 µM against promastigotes, and 6.02 µM ± 0.52, 3.55 ± 0.22 µM and 6.23 ± 0.13 µM against amastigotes, respectively. Oral administration of compounds F12 and F27 entailed >85% reduction in organ parasite burden in L. donovani-infected BALB/c mice and hamsters, by promoting host-protective Th1 cytokine response. In host J774 macrophages, mechanistic studies revealed inhibition of PI3K/Akt/CREB axis, resulting in a decrease of IL-10 versus IL-12 release upon F27 treatment. In silico docking studies conducted with lead compound, F27 demonstrated plausible inhibition of Leishmania prolyl-tRNA synthetase, which was validated via detection of decreased proline levels in parasites and induction of amino acid starvation, leading to G1 cell cycle arrest and autophagy-mediated programmed cell death of L. donovani promastigotes. Structure-activity analysis and study of pharmacokinetic and physicochemical parameters suggest oral availability and underscore F27 as a promising lead for anti-leishmanial drug development.

Development of protein fortified mango based ready-to-serve beverage.

Fruit drinks contain negligible amount of protein as nutritional component. Fortification of fruit drinks with protein is a challenge due to protein stability in acidic and ionic environment. Mango ready-to-serve (RTS) beverage was fortified with modified whey protein and its rheological properties were studied. Whey protein was hydrolysed with papain to improve its stability in acidic medium. The water holding capacity of whey protein increased about two times after hydrolysis. Hydrolysed and native whey protein was used at 2, 3 and 4% levels for fortification of mango based RTS beverage. Addition of hydrolysed whey protein at all the three levels did not significantly change the flow behaviour of the beverage. Native whey protein fortification resulted in precipitation; however, addition of hydrolysed whey protein led to stable beverage formulation at all the three levels. Hydrolysed whey protein imparted slight bitter taste to the RTS beverage, which was masked by ß-cyclodextrin @ 0.15% of total protein. The mango RTS beverage with 3.0% hydrolysed whey protein was found acceptable with good sensory appeal and stability during thermal processing as well storage in glass bottles.