Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

A series of novel neocryptolepine–rhodanine hybrids (9a,b, 11a–d, 14, and 16a,b) have been synthesized by combining neocryptolepine core 5 modified at the C-11 position with rhodanine condensed with the appropriate aryl/hetero aryl aldehydes. Based on these findings, the structures of the hybrids were confirmed by spectral analyses. By employing the MTT assay, all hybrids were tested for their in vitro antiproliferative activity against two cancer cell lines, including MDA-MB-231 (human breast) and HepG-2 (hepatocellular carcinoma). Interestingly, the IC₅₀ values of all hybrids except 9b and 11c showed activity comparable to the standard anticancer drug, 5-fluorouracil, against HepG-2 cancer cells. Furthermore, the cytotoxicity of all the synthesized hybrids was investigated on a normal skin human cell line (BJ-1), and the results showed that these compounds had no significant cytotoxicity toward these healthy cells at the highest concentration used in this study. This study also indicated that the active hybrids exert their cytotoxic activity via the induction of apoptosis. A molecular docking study was used to shed light on the molecular mechanism of their anticancer activity. The docking results revealed that the hybrids exert their mode of action through DNA intercalation. Furthermore, in silico assessment for pharmacokinetic properties was performed on the most potent compounds, which revealed candidates with good bioavailability, high tolerability with cell membranes, and positive drug-likeness values.

Background: Type 2 diabetes mellitus (T2DM) presents a significant global health challenge, with obesity being a major contributing risk factor alongside genetic and non-genetic elements. Current treatments focus on reducing hyperglycemia and preventing T2DM progression, often involving drug combinations for enhanced efficacy. This study introduces two novel nitrogen-containing heterocyclic scaffolds: neocryptolepine–thiazolidinedione (NC-TZD) 8 and acridine–thiazolidinedione (AC-TZD) 11. Methods: These compounds were synthesized and characterized using various spectroscopic techniques. Their antihyperglycemic and antihyperlipidemic effects were assessed in an obesity-induced zebrafish model. Hyperglycemia was induced by immersing zebrafish in 100 mM glucose monohydrate for two weeks. Fish were then divided into groups receiving either 20 mg or 80 mg of the drugs per kg of body weight, alongside negative and positive control groups. Results: Both doses of hybrids 8 and 11 effectively restored glucose, triglyceride, insulin, and nuclear factor kappa beta (nfκβ) mRNA levels to normal. However, only the lower doses restored peroxisomal acyl-CoA oxidase (acox1) mRNA levels, with higher doses proving less effective. A molecular modeling study supported the antidiabetic potential of hybrids 8 and 11, suggesting interactions with target proteins PPAR-α and acox1. In silico ADMET analysis revealed promising oral bioavailability and drug likeness for both compounds. Conclusions: The findings indicate that both hybrids exhibit significant antihyperglycemic and antihypertriglyceridemic effects, particularly at lower doses. These results highlight the promising therapeutic potential of these novel oral bioavailable compounds in managing T2DM. Further research is warranted to elucidate their mechanisms of action.

Background: Type 2 diabetes mellitus (T2DM) and hyperlipidemia are interrelated metabolic disorders that significantly increase cardiovascular risk. Thiazolidinediones are known insulin sensitizers, whereas quinoline derivatives possess diverse pharmacological activities. To explore their complementary activity, we designed a novel hybrid compound integrating a thiazolidinedione core with a quinoline moiety via a carbon spacer. Materials and Methods: The hybrid molecule was synthesized through a straightforward route and structurally confirmed by spectroscopic analyses. Zebrafish (Danio rerio) were employed as an in vivo model, with hyperglycemia induced by immersion in 100 mM glucose monohydrate for 12 days. Fish were divided into treatment groups receiving 20 or 80 mg/kg of the compound, alongside the controls. Biochemical parameters (glucose, triglycerides, insulin) and gene expression levels (NF-κB, ACOX1, ACCα) were assessed. In silico docking was conducted to predict molecular interactions. Results: Treatment with the hybrid compound significantly restored glucose, triglyceride, and insulin levels. High-dose administration suppressed NF-κB expression and normalized ACOX1 levels, while both low- and high-dose treatments downregulated ACCα compared with untreated hyperglycemic controls. Computational studies supported multitarget activity through predicted binding to PPAR-α and ACOX1. Conclusions: Quinoline-Thiazolidine-2,4-Dione demonstrated strong antihyperglycemic and antihypertriglyceridemic activities in zebrafish models, supported by in silico validation.