Abbas Hassan

Receptor tyrosine kinases (RTKs), including VEGFR-2, EGFR, and c-MET, have been recognized as promising oncogenic targets in tumor progression, invasion, and metastasis. Developing multitarget inhibitors that block these kinases simultaneously offers a powerful strategy to suppress angiogenesis and oncogenic signaling, while potentially minimizing adverse effects. A new series of benzothiazole- and benzimidazole-based urea derivatives was designed rationally through scaffold modification and linker optimization to enhance multikinase inhibition. Moreover, in vitro evaluation of the newly synthesized series revealed that compounds 6a–c, 7a, 12a, 17, and 18 exhibited multitarget inhibitory potential. Additionally, 11b, 12a, 17, and 18 showed the best antiproliferative potential against MCF7 and A549 cells, as indicated by the antiproliferative assay. While compounds 6b, 7a, 17, and 18 demonstrated negligible cytotoxicity against normal HEK-293 cells, with IC₅₀ values exceeding 100 μM (>100 μM). Furthermore, the antiangiogenic efficacy of 11b, 12a, 17, and 18 was validated through CAM assays, which markedly suppressed neovascularization. Molecular docking revealed efficient occupation of 6b, 7a, 12a, 17, and 18 with key binding pockets across VEGFR-2, EGFR, and c-Met. The 200 ns molecular dynamics (MD) simulations confirmed the stability of the 4ASD–6b complex with enhanced flexibility compared to sorafenib. Collectively, these findings establish benzothiazole, benzimidazole, and quinoline-based urea hybrids as promising leads with enhanced multikinase selectivity and reduced toxicity compared to existing inhibitors, offering strong therapeutic potential in angiogenesis-driven cancers.

Antimicrobial resistance is a global health threat affecting millions of people worldwide. The situation has been exacerbated by the emergence of β-lactamase enzymes that can hydrolyze the β-lactam rings within the antibiotics. This makes antibiotics incapable of preventing bacterial infections. The abuse of β-lactam antibiotics is instigating bacterial resistance, thus causing the antibiotics to fail. There is a need to develop newer drugs that can tackle these β-lactamases and overcome bacterial infections. Thienopyrimidines have exhibited diverse biological activities as promising potent antibacterial agents. We synthesized a wide array of substituted thienopyrimidines using a highly divergent approach to introduce different groups involving Suzuki and Sonogashira coupling reactions, aromatic nucleophilic substitution, and alkylation reactions. Novel thienopyrimidines were tested against Pseudomonas aeruginosa and Staphylococcus aureus, showed inhibitory activity, and were further tested for β-lactamase activity. In-depth investigation revealed that 4-(2-(tert-butyl)­thieno­[2,3-d]­pyrimidin-4-yl)­morpholine demonstrated exceptional results compared to cefixime (control). To evaluate the compound’s potency in combination therapy, synergistic effects were observed when imipenem was administered alongside our potent compound, resulting in a significantly enhanced minimum inhibitory effect against clinical isolates of S. aureus. The findings from this study hold substantial pharmacological significance in addressing the growing threat of bacterial resistance, particularly associated with β-lactamase enzymes.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and cognitive decline, associated with synaptic loss and degeneration of cholinergic neurons. New multitarget inhibitors for monoamine oxidase (MAO) and cholinesterase (ChE) enzymes are emerging as a potential treatment strategy for AD. Herein, we synthesized a series of N-benzyl-substituted biaryl phthalimide derivatives (3a-3m) encompassing potentially therapeutically active arenes/heteroarenes to serve as multitarget compounds for treating AD. To improve their binding affinity as well as inhibitory activity against ChE and MAO target proteins, comparable molecular structures were synthesized bearing electron-donating, electron-withdrawing, heterocyclic, and fluorinated moieties for a comprehensive SAR. In vitro evaluation of synthesized compounds against cholinesterases (AChE/BChE) and monoamine oxidases (MAO-A/MAO-B) revealed that compound 3e had good potency against AChE (IC₅₀ = 0.24 μM) and BChE (IC₅₀ = 6.29 μM), while compound 3f had the highest inhibition of MAO-B (IC₅₀ = 0.09 μM). Selected compounds (3e,f) showed no cytotoxicity against the neuroblastoma cell line (SH-SY5Y) and normal human embryonic HEK-293 cells. Moreover, they showed high blood-brain barrier penetration (PAMPA assay) and reversible MAO-B inhibitory activity (ex vivo). In molecular docking studies, compounds 3e and 3f displayed the highest binding affinity with ChEs and MAO-B, respectively. In silico ADMET studies and MD simulation studies were also carried out for the most potent derivatives (3e and 3f), suggesting their strong potential as anti-Alzheimer agents.

Sulfamoyl-benzamides were found to be selective inhibitors against h-NTPDases1, -2, -3, and -8 in sub-micromolar concentration, for instance, compound 3i was found to be the most potent inhibitor of h-NTPDase1 (IC50 = 2.88 ± 0.13 μM).

In this study various of thieno[3,2‐d]pyrimidine derivatives have been synthesized by treating different secondary amines through aromatic nucleophilic substitution reaction (S_NAr) followed by Suzuki reaction with aryl and heteroaryl boronic acids. A bis‐Suzuki coupling was also performed to generate bis‐aryl thienopyrimidine derivatives. The synthesized compounds were screened for the hydrolytic activity of h‐NTPdase1, h‐NTPdase2, h‐NTPdase3, and h‐NTPdase8. The compound N‐benzyl‐N‐methyl‐7‐phenylthieno[3,2‐d]pyrimidin‐4‐amine 3 j selectively inhibits the activity of h‐NTPdase1 with IC₅₀ value of 0.62±0.02 μM whereas, the compound 4 d was the most potent inhibitor of h‐NTPdase2 with sub‐micromolar IC₅₀ value of 0.33±0.09 μM. Similarly, compounds 4 c and 3 b were found to be selective inhibitors for isozymes h‐NTPdase3 (IC₅₀=0.13±0.06 μM) and h‐NTPdase8 (IC₅₀=0.32±0.10 μM), respectively. The molecular docking study of the compounds with the highest potency and selectivity revealed the interactions with the important amino acid residues.

Journal of the Chemical Society of Pakistan (JCSP) is a bimonthly Journal which publishes results of original, unpublished research work and review articles in all fields of Chemistry.