Synthesis and biological evaluation of polyhydroxylated oxindole derivatives as potential antileishmanial agent
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Synthesis
In the present work, four-steps synthetic strategies are adapted for the preparation of polyhydroxylated oxindole derivative (1). Additionally, we have synthesized dimethyl- and difluoro- substituted stilbenic oxindole derivatives in order to obtain the importance of substitution on stilbene nucleus. The representation describing the routes of its synthesis is depicted in the Scheme 1A. Initially, we undertook the synthesis of the intermediate, 5-bromo bis-arylidene oxindole (4), using McMurry
Anti-proliferative and cytotoxic activities of 1 against L. donovani promastigotes and murine splenocytes
At first, the anti-proliferative activities of the five molecules i.e. 7a, 7b, 7c, 10 and 11 were screened against L. donovani AG83 (MHOM/IN/83/AG83) promastigotes via MTT assay. Based on the result of the assay, it could be stated that 7a and 10 showed moderate antileishmanial activities with IC50 values of 31 µM and 47.2 µM, respectively, in comparison to 7b, 7c and 11 (IC50 values 225 µM, 220 µM and 200 µM respectively) (Fig. 1A), which are indeed less active.
To enhance the antileishmanial
Arrest of cell cycle progression in L. donovani promastigotes
The amount of pseudo-hypodiploid cells were quantified by labelling them with Propidium Iodide (PI) and analysing in a flow cytometer. As the amount of bound dye correlates with the DNA content of a given cell, thus DNA fragmentation in apoptotic cells translates into fluorescence intensity lower than that of G0/G1 cells, depicting a sub-G0/G1 peak.17 At 24 h of treatment with 1, the proportion of cells in the sub-G0/G1 phase (P5) was found to be 6.79%, as compared with 2.61% of the control
Induction of oxidative stress in L. Donovani promastigotes
In Leishmania, oxidative stress is proposed to be accountable for one of the apoptotic processes.18 Treatment of promastigotes with 1 could successfully increase ROS levels in a time-dependent manner, causing oxidative damage to the promastigotes. At 6 h, 1 treatment resulted in more than threefold increase in ROS levels with respect to the control culture (Fig. 3 in SI: S11).
Externalization of phosphatidylserine in treated L. Donovani promastigotes
In metazoan and unicellular cells, a ubiquitous translocation of phosphatidylserine occurs from the inner to the outer leaflet of the plasma membrane during apoptosis.19 In order to study whether the promastigote death triggered by 1 is via apoptosis or necrosis, the cells (24 and 48 h with an IC50 concentration of 15 µM) were double stained with PE-conjugated Annexin V and 7AAD. The externalization of phosphatidylserine residues was observed in 10.98% (early apoptotic; Annexin V only) and in
DNA condensation and deposition of lipids in L. donovani promastigotes
The apoptosis-inducing capacity of 1 was further confirmed by chromatin condensation in treated promastigotes using DAPI staining with fluorescence microscopy. The treated promastigotes displayed typical characteristics of apoptotic cells viz. condensed chromatin material and blebbed nuclei (large white arrows), whereas the control parasites exhibited discrete nuclei (blue spots).
Another prominent effect on the biochemical property of the treated promastigotes was the accumulation of lipid
Inhibition of intracellular amastigotes and induction of NO production in infected macrophages
The anti-promastigote effect of 1 motivated us to investigate the effect of this molecule against intracellular amastigotes, as these are the replicative form of the parasites, infectious to the mammalian host. Significantly, 50% inhibition of intracellular amastigotes was detected at a concentration of 1 µM at 48 h, much lower than the IC50 concentration against promastigotes. Furthermore, the treatment was found to induce a substantial release of nitric oxide in infected macrophages, one of
Acknowledgements
M.Y. and D.M acknowledge CSIR & ICMR, India, respectively for a research fellowship. S.A. acknowledges the Science and Engineering Research Board, Govt. of India (Project No. SR/S1/OC-101/2012) for financial support. C.P also acknowledges DST-FIST, Govt. of India [Ref: SR/FST/LS1-001/2014] and DBT-BOOST, Govt. of West Bengal [Ref: 49 (11)/BT (Estt)/1P-4/2013 (Part 1)] for financial support. Thanks are also due to Tanojit Sur for his assistance in FACS analysis.
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2021, Biomedicine and PharmacotherapyCitation Excerpt :These versatile compounds are credited to possess an extensive array of biochemical applications with reportedly a multidisciplinary range of biological effects. Quite significant number of research groups have formulated, designed, synthesized, and evaluated oxindole derivatives for countless biological activities, that include anticancer [17], antimicrobial [18], α-glucosidase inhibition [19], rheumatoid arthritis [20], intraocular pressure reducing abilities [21], tyrosinase inhibition [22], PAK-4 (Serine/threonine-protein kinase) inhibition [23], antileishmanial [24], antimycobacterial [25], antioxidative [26], and antiviral properties [27]. A concise summary of the relationship between activity and substituent position concerning oxindole compounds’ pharmacological activities is depicted in Fig. 5.
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These authors contributed equally to this work.