Sirish Kumar Ippagunta

Malaria is a life‐threatening disease that affects tropical and subtropical regions worldwide. Various drugs were used to treat malaria, including artemisinin and derivatives, antibiotics (tetracycline, doxycycline), quinolines (chloroquine, amodiaquine), and folate antagonists (sulfadoxine and pyrimethamine). Since the malarial parasites developed drug resistance, there is a need to develop new chemical entities with high efficacy and low toxicity. In this context, 1,2,4,5‐tetraoxanes emerged as an essential scaffold and have shown promising antimalarial activity. To improve activity and overcome resistance to various antimalarial drugs; 1,2,4,5‐tetraoxanes were fused with various aryl/heteroaryl/alicyclic/spiro moieties (steroid‐based 1,2,4,5‐tetraoxanes, triazine‐based 1,2,4,5‐tetraoxanes, aminoquinoline‐based 1,2,4,5‐tetraoxanes, dispiro‐based 1,2,4,5‐tetraoxanes, piperidine‐based 1,2,4,5‐tetraoxanes and diaryl‐based 1,2,4,5‐tetraoxanes). The present review aims to focus on covering the relevant literature published during the past 30 years (1992–2022). We summarize the most significant in vitro, in vivo results and structure–activity relationship studies of 1,2,4,5‐tetraoxane‐based hybrids as antimalarial agents. The structural evolution of different hybrids can provide the framework for the future development of 1,2,4,5‐tetraoxane‐based hybrids to treat malaria.

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins 1a–b, a number of α-amino acids 2a–e and (E)-2-aryl-1-nitroethenes 3a–e in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation conditions. The structure elucidation of all the synthesized spirooxindoles were done using ¹H and ¹³C NMR and HRMS spectral analysis. The single crystal X-ray crystallographic study of compound 4l was used to assign the stereochemical arrangements of the groups around the pyrrolidine ring in spiro[pyrrolidine-2,3′-oxindoles] skeleton. The in vitro anticancer activity of spiro[pyrrolidine-2,3′-oxindoles] analogs 4a–w against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines shows promising results. Out of the 23 synthesized spiro[pyrrolidine-2,3′-oxindoles], while five compounds (4c, 4f, 4m, 4q, 4t) (IC₅₀ = 34.99–47.92 µM; SI = 0.96–2.43) displayed significant in vitro anticancer activity against human lung (A549) cancer cell lines, six compounds (4c, 4f, 4k, 4m, 4q, 4t) (IC₅₀ = 41.56–86.53 µM; SI = 0.49–0.99) displayed promising in vitro anticancer activity against human liver (HepG2) cancer cell lines. In the case of lung (A549) cancer cell lines, these compounds were recognized to be more efficient and selective than standard reference artemisinin (IC₅₀ = 100 µM) and chloroquine (IC₅₀ = 100 µM; SI: 0.03). However, none of them were found to be active as compared to artesunic acid [IC₅₀ = 9.85 µM; SI = 0.76 against lung (A549) cancer cell line and IC₅₀ = 4.09 µM; SI = 2.01 against liver (HepG2) cancer cell line].