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Diabetes mellitus (DM) and related complications continue to exert a significant burden on health care systems globally. Although conventional pharmacological therapies are beneficial in the management of this metabolic condition, it is still necessary to seek novel potential molecules for its management. On this basis, we have synthesised and evaluated the anti-diabetic properties of four novel thiazolidinedione (TZD)-derivatives. The TZD derivatives were synthesised through the pharmacophore hybridisation strategy based on N-arylpyrrole and TZD. The resultant derivatives at different concentrations were screened against key enzymes of glucose metabolism and glucose utilisation in the liver (HEP-G2) cell line. Additionally, peroxisome proliferator-activated receptor-γ activation was performed through docking studies. Docking of these molecules against PPAR-γ predicted strong binding, similar to that of rosiglitazone. Hence, TZDD2 was able to increase glucose uptake in the liver cells as compared to the control. The enzymatic inhibition assays showed a relative inhibition activity; with all four derivatives exhibiting ≥ 50% inhibition activity in the α-amylase inhibition assay and a concentration dependent activity in the α-glucosidase inhibition assay. All four derivatives exhibited ≥30% inhibition in the aldose reductase inhibition assay, except TZDD1 at 10 µg/mL. Interestingly, TZDD3 showed a decreasing inhibition activity. In the dipeptidyl peptidase–4 inhibition assay, TZDD2 and TZDD4 exhibited ≥20% inhibition activity.

A series of 25 new benzothiazole–urea–quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (1H and 13C NMR and IR) and by mass spectrometry (HRMS). In vitro evaluation of these hybrid compounds for their antitubercular inhibitory activity against the Mycobacterium tuberculosis H37Rv pMSp12::GPF bioreporter strain was undertaken. Of the 25 tested compounds, 17 exhibited promising anti-TB activities of less than 62.5 µM (MIC90). Specifically, 13 compounds (6b, 6g, 6i–j, 6l, 6o–p, 6r–t, and 6x–y) showed promising activity with MIC90 values in the range of 1–10 µM, while compound 6u, being the most active, exhibited sub-micromolar activity (0.968 µM) in the CAS assay. In addition, minimal cytotoxicity against the HepG2 cell line (cell viability above 75%) in 11 of the 17 compounds, at their respective MIC90 concentrations, was observed, with 6u exhibiting 100% cell viability. The hybridization of the quinoline, urea, and benzothiazole scaffolds demonstrated a synergistic relationship because the activities of resultant hybrids were vastly improved compared to the individual entities. In silico ADME predictions showed that the majority of these compounds have drug-like properties and are less likely to potentially cause cardiotoxicity (QPlogHERG > −5). The results obtained in this study indicate that the majority of the synthesized compounds could serve as valuable starting points for future optimizations as new antimycobacterial agents.

A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a cultured T. b. rhodesiense STIB900 strain. Several of these compounds (4a–g) displayed good antiplasmodium activities (IC50 = 0.20–0.62 µM) that were comparable to the reference drugs, while their antitrypanosomal activity was moderate (4e was 2-fold more active than primaquine and was also the most active (IC50 = 7.01 µM) against T. b. rhodesiense and also exhibited excellent aqueous solubility (>200 µM) at pH 7.