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.

Antibiotic resistance is increasing at such an alarming rate that it is now one of the greatest global health challenges. Undesirable toxic side-effects of the drugs lead to high rates of non-completion of treatment regimens which in turn leads to the development of drug resistance. We report on the development of delivery systems that enable antibiotics to be toxic against bacterial cells while sparing human cells. The broad-spectrum fluoroquinolone antibiotic moxifloxacin (Mox) was successfully conjugated to poly(ethylene glycol) (PEG) which was further encapsulated into the hydrophobic poly(ε-caprolactone) (PCL) nanoparticles (NPs) with high efficiency, average particle size of 241.8 ± 4 nm and negative zeta potential. Toxicity against erythrocytes and MDBK cell lines and drug release in human plasma were evaluated. Hemocompatibility and reduced cytotoxicity of the PEG–Mox and PCL(PEG–Mox) NPs were demonstrated in comparison to free Mox. Antimicrobial activity was assessed against drug sensitive and resistant: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The antibacterial activity of Mox was largely maintained after conjugation. Our data shows that the toxicity of Mox can be effectively attenuated while, in the case of PEG–Mox, retaining significant antibacterial activity. At the conditions employed in this study for antimicrobial activity the encapsulated conjugate (PCL(PEG–Mox) NPs) did not demonstrate, conclusively, significant antibacterial activity. These systems do, however, hold promise if further developed for improved treatment of bacterial infections.

Pancreatic cancer (PC) is one of the most aggressive solid malignancies with poor treatment response and low survival rates. Herbal medicines such as betulinic acid (BA) have shown potential in treating various solid tumours, but with limitations that can be circumvented by polymer-drug conjugation. Polyethylene glycol-BA (PEG-BA) polymer-drug conjugate has previously shown selective anticancer activity against PC cells. Here, we elucidate the mechanism of cell death and the cell death pathway, anti-inflammatory and antioxidant activities of PEG-BA. PEG-BA induced apoptotic cell death by arresting MIA-PaCa-2 cells in the Sub-G₁ phase of the cell cycle compared with BA and untreated cells (39.50 ± 5.32% > 19.63 ± 4.49% > 4.57 ± 0.82%). NFκB/p65 protein expression was moderately increased by PEG-BA (2.70 vs. 3.09 ± 0.42 ng/mL; p = 0.1521). However, significant (p < 0.05) overexpression of the proapoptotic genes TNF (23.72 ± 1.03) and CASPASE 3 (12,059.98 ± 1.74) compared with untreated cells was notable. The antioxidant potential of PEG-BA was greater (IC₅₀ = 15.59 ± 0.64 µM) compared with ascorbic acid (25.58 ± 0.44 µM) and BA-only (>100 µM) and further confirmed with the improved reduction of hydroperoxide levels compared with BA-only (518.80 ± 25.53 µM vs. 542.43 ± 9.70 µM). In conclusion, PEG-BA activated both the intrinsic and extrinsic pathways of apoptosis and improved antioxidant activities in PC cells, suggesting enhanced anticancer activity upon conjugation.

Drug delivery systems involving polymer therapeutics enhance drug potency by improved solubility and specificity and may assist in circumventing chemoresistance in pancreatic cancer (PC). We compared the effectiveness of the naturally occurring drug, betulinic acid (BA), alone and in a polymer conjugate construct of polyethylene glycol (PEG), (PEG–BA), on PC cells (MIA PaCa-2), a normal cell line (Vero) and on peripheral blood mononuclear cells (PBMCs). PEG–BA, was tested for its effect on cell death, immunomodulation and chemoresistance-linked signalling pathways. The conjugate was significantly more toxic to PC cells (p < 0.001, IC₅₀ of 1.35 ± 0.11 µM) compared to BA (IC₅₀ of 12.70 ± 0.34 µM), with a selectivity index (SI) of 7.28 compared to 1.4 in Vero cells. Cytotoxicity was confirmed by increased apoptotic cell death. PEG–BA inhibited the production of IL-6 by 4–5.5 fold compared to BA-treated cells. Furthermore, PEG–BA treatment of MIA PaCa-2 cells resulted in the dysregulation of crucial chemoresistance genes such as WNT3A, TXNRD1, SLC2A1 and GATA3. The dysregulation of chemoresistance-associated genes and the inhibition of cytokines such as IL-6 by the model polymer construct, PEG–BA, holds promise for further exploration in PC treatment.

Synthetic chemotherapeutics have played a crucial role in minimizing mostly palliative symptoms associated with cancer; however, they have also created other problems such as system toxicity due to a lack of specificity. This has led to the development of polymer-drug conjugates amongst other novel drug delivery systems. Most of the formulations designed using delivery systems consist of synthetic drugs and face issues such as drug resistance, which has already rendered drugs such as antibiotics ineffective. This is further exacerbated by toxicity due to the long-term use. Given these problems and the fact that conjugation of synthetic compounds to polymers has been relatively slow with no formulation on the market after a decade of extensive studies, the focus has shifted to using this platform with medicinal plant extracts to improve solubility, specificity and increase drug release of medicinal and herbal bioactives. In recent years, various plant extracts such as flavonoids, tannins and terpenoids have been studied extensively using this approach. The success of formulations developed using novel drug-delivery systems is highly dependent on the tumour microenvironment especially on the enhanced permeability and retention effect. As a result, the compromised lymphatic network and ‘leaky’ vasculature exhibited by tumour cells act as a guiding principle in the delivery of these formulations. This review focuses on the state of the polymer-drug conjugates and their exploration with natural compounds, the progress and difficulties thus far, and future directions concerning cancer treatment.