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

• Published in: European journal of medicinal chemistry 2023-09, Vol.257, p.115524-115524, Article 115524
• Main Authors: Ansari, Alisha, Seth, Anuradha, Dutta, Mukul, Qamar, Tooba, Katiyar, Sarita, Jaiswal, Arvind K., Rani, Ankita, Majhi, Swetapadma, Kumar, Mukesh, Bhatta, Rabi S., Guha, Rajdeep, Mitra, Kalyan, Sashidhara, Koneni V., Kar, Susanta
• Format: Article
• Language: English
• Subjects: Acetamide; Apoptosis; Autophagy; Cytokine response; Quinazolinone; Visceral leishmaniasis (VL)
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115524

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. [Display omitted] •A series of quinazolinone-based acetamide derivatives (F1-F33) were synthesized.•Two compounds, F12 and F27 exhibited maximum in vitro anti-leishmanial activity.•Compounds F12 and F27 significantly reduced parasite burden in L.d-infected animals.•Compound F27 inhibited host PI3K/Akt/CREB axis-mediated IL-10 secretion.•Compound F27 induced autophagy-mediated apoptosis in L. donovani promastigotes.