Medicinal Chemistry Research最新文献

Parkinson’s disease (PD) is the 2nd most prevalent neurodegenerative illness globally, characterized by tremors, stiffness, bradykinesia, and postural imbalances. In PD degradation of dopaminergic neuronal cells in the substantia nigra, results in decreased dopamine levels in the striatum and which is achieved by various neurotoxins and MPTP remain most effective in various animal models. The MPTP-induced rodent model, which has been commonly utilized in PD research because of its practicality and reduced ethical considerations, also replicates all characteristics of human PD. MPTP potentially affects humans, monkeys, rats, zebrafish, and Caenorhabditis elegans. MPTP causes neurotoxicity by forming its toxic metabolite MPP⁺ through MAO-B (monoamine oxidase B) enzyme and entering into the brain through the dopamine transporter and causing aggregation of alpha-synuclein, inhibition of mitochondrial complex I enzyme, formation of free radicals, release of proinflammatory factors, elevation in glutamate may affect mitochondria, therefore ultimately causing dopaminergic cell death. Recent studies found significant decreases in various neurobehavioural functions, along with low dopamine levels in the brain. The results of recent studies employing this model are excellent. The model has the limitation that chronic MPTP administration causes rapid neuron death and lacks α-synuclein aggregation and Lewy formation. Future research should focus on replicating all Parkinsonian symptoms identical to human PD as a focus for therapy.

β-Lactam derivatives have inspired chemists to develop synthetic methods, given the prevalence of β-lactam scaffolds in numerous existing drugs. Recently, the incorporation of β-lactam derivatives into diverse heterocycles using novel pharmacophoric hybridization strategies has led to the development of compounds with significant medicinal applications. The five-membered heterocycles incorporating heteroatoms, such as nitrogen, oxygen, and sulfur, influence their chemical and biological properties. Advances in synthetic strategies, including transition metal catalysis, Staudinger cycloaddition, the Kinugasa reaction, halocyclization, and functionalization using available β-lactam drugs, have facilitated the construction of a variety of β-lactam scaffolds. This article presents an in-depth review of the latest methods for the synthesis of five-membered heterocycles (N/O/S) linked β-lactams from 2020–2025. This review aims to support researchers in designing and developing novel β-lactam linked with five-membered heterocycles (N/O/S) with enhanced therapeutic efficacy by delving into recent advances (2020–2025) in synthetic endeavors for β-lactams.

Carbon monoxide (CO) is an endogenously produced gaseous signaling molecule that has been shown to have therapeutic values. In studying CO pharmacology, dose dependency has not been properly studied in most, if not all, such work. Part of the reason is the difficulty in determining the solution concentration of a gaseous molecule (CO) with limited water solubility (~1 mM). Along this line, CO solution prepared at a pre-determined concentration has been widely used in studying CO pharmacology. However, different from making a solution of a non-volatile small-molecule drug, CO is expected to quickly escape from the solution, leading to unknown concentrations and an intractable scenario for dose-dependency studies. In this study, we hope to help define the boundary conditions by studying the concentration decay profiles of CO in solution at a pre-determined concentration. Results from such studies will be very important foundational information for future dose-dependency studies of CO pharmacology.

Herein, Vilsmeier reaction-based synthesized 1H-indole-3-carbaldehyde was utilized in the azines derivatives (6a-d) synthesis through C-5 halogen-substituted oxindoles and their anticancer effect against human cancer cells, as reported. The effect of halogens at C-5 of synthesized compounds (6a-d) on human cancer cells was demonstrated by the National Cancer Institute-Developmental Therapeutics Program, USA. The effect of halogens was notably cytotoxicity against cells, but the bromo-substituted compound 6c was further analyzed under five-dose screening at different concentrations, including 10⁻⁴, 10⁻⁶, 10⁻⁵, 10⁻⁷, and 10⁻⁸M. It was concluded that EKVX and UACC-257 cell lines were shown to be −6.58 (lowest) and −4.65 (highest) GI₅₀ at log₁₀ high concentration −4.0, respectively. However, TGI values for RXF and UACC-257 cell lines were shown to be −5.12 (lowest) and −4.0 (more than) at the same concentrations. The lowest LC₅₀ value was calculated at −4.50 for RXF 393 cell line, while the highest LC₅₀ value was noted at less than −4.0 for the T-47D cell of breast cancer at log₁₀ high concentration −4.0, respectively. The aim of research is to demonstrate the halogen’s effects on human cancer cells whenever it is attached at a suitable position at C-5 of the oxindole ring. In the future it could be used as lead molecule in clinical in-vivo investigations on human lung cancer.

Glyoxalase I (Glo-I), a key enzyme involved in cellular detoxification, overexpression of which is implicated in cancer cell survival and proliferation, is a promising therapeutic target. Al-Balas et al. discovered NSCI153166 (IC₅₀ = 0.97 μM) as a potent Glo-I inhibitor through virtual screening of the NCI database. The compound was previously reported as a bis-imine derivative 1; however, structural elucidation for the in-house synthesized compound revealed it to be a 1,2-disubstituted benzimidazole 2. Surprisingly, both compounds exhibited comparable inhibitory activities. To explore structure-activity relationships, 31 analogues of both scaffolds were synthesized and evaluated against Glo-I. Key findings demonstrated that in the benzimidazole series, both aromatic rings and hydroxyl groups are essential for activity, as removal of the substituted benzyl ring and variations in the phenyl ring substituents led to a complete loss of activity, highlighting the importance of both aromatic rings and the hydroxyl groups, confirmed by docking studies showing crucial interactions of these groups with the Glo-I active site. In the bis-imine series, while modifications to the linker and phenyl rings were tolerated, the scaffold proved to be more fruitful. Notably, meta- and para-substituted bis-imines 22 (IC₅₀ = 0.86 μM) and 23 (IC₅₀ = 0.89 μM) exhibited potent activity, comparable to NSCI153166. However, docking studies of 23 indicated a lack of zinc chelation, suggesting potential for optimization through zinc-chelating substituents. The phenyl linker proved superior to the aliphatic ethylene linker. While both scaffolds show promise as Glo-I inhibitors, further optimization is necessary to enhance potency by exploring alternative linker groups and structural modifications to improve zinc binding affinity, ultimately leading to the development of novel Glo-I inhibitors for cancer therapy.

Modeling cationic small-molecule inhibitors of G-quadruplex structures faces controversial opinions as to whether stabilization of the complex can occur by the interaction of the inhibitor with the negatively charged phosphate backbone. The challenge has been taken here of bringing light on such a awful situation by disentangling the energies of interaction of G-quadruplex residues with the inhibitor in a series of representative G-quadruplex complexes. The problem was addressed to computer simulations in the lack of suitable experimental approaches. It emerged that the phosphate contribution can range from dominating to nil, according to whether, in a dynamic course, the inhibitor cationic center can get close to a phosphate group or remain out of the range of coulombic attraction from all them, thus providing guidelines for tailoring the inhibitor toward the best possible stabilization of the complex.

Graphical Abstract

With two quindoline molecules (top hot pink, bottom green) as inhibitors per G-quadruplex structure, stabilization of the complex by phosphate interaction with the quindoline cationic center is highlighted by interrupted lines.

Diphenyl ether and quinoline based compounds have been reported to show antibacterial activity. Against Mycobacterium tuberculosis, drug targets inhibited by diphenyl ether compounds are reportedly different from those perturbed by quinoline based antitubercular hits/drugs. Herein, we conceptualized and synthesized novel molecules incorporating quinoline and diphenyl ether moieties. The antitubercular property of the synthesized compounds were measured in vitro using Tween 80 and Tyloxapol supplemented growth media. Compounds in this study generally showed sub micromolar antitubercular activity in tween 80/albumin supplemented growth medium, and moderate to poor activity in tyloxapol/casitone supplemented growth medium. Compound 4e, havin a trimethylenediamine moiety and low melting point of 68 °C, emerged as the hit compound, possessing MIC₉₀ value of 0.2 µM. 4e is non-cytotoxic when tested against normal human cell line, exhibiting CC₅₀ value > 20 µM.

Cytotoxicity of a series of nicotinonitrile-based derivatives with the molecular target and apoptosis activity against PC-3 cells was described. Compound 7b exhibited remarkable cytotoxicity against MCF-7 and PC-3 cells with IC₅₀ values of 3.58 μM and 3.60 μM, respectively. Interestingly, compounds 4k and 7b had potent PIM-1 kinase inhibition with IC₅₀ values of 21.2 nM and 18.9 nM, respectively, with inhibition of 92.7 and 96.4% compared to Staurosporine (IC₅₀ = 16.7 nM, with 95.6% inhibition). Moreover, compound 7b significantly activated apoptosis in PC-3 cells, increasing the apoptotic cell death, increasing total apoptosis by 34.21% compared to 0.9% in control cells, and arresting the cell cycle at the G1 pahse. In vivo model of SEC-bearing mice confirmed the anticancer activity of compound 7b by having 42.9% compared to the 5-FU treatment of 54.2%; it maintained the physiological activity of hematological and biochemical parameters. Molecular docking effectively sheds insight into the mechanism of PIM-1 kinase inhibition by revealing the binding interactions between the lead chemical 7b and the PIM-1 protein. The results showed that compound 7b showed promise as a chemotherapeutic drug targeting PIM-1 for the treatment of breast cancer.

The investigation of natural products and their derivatives or analogues represents a critical avenue for the discovery of novel drug candidates. Piperlongumine (PL), a natural alkaloid, was originally isolated from the roots of Piper longum L., and has been reported to possess various biological activities. In this study, we designed and synthesized a total of 24 PL analogues by retaining the trimethoxystyryl group, whereas the piperidinone part of PL was replaced by indoline or 1,2,3,4-tetrahydroquinoline. The synthesized analogues were characterized by ¹H NMR, ¹³C NMR, and HRMS analysis. The in vitro anticancer activity of the compounds against lung cancer cells A549, breast cancer cells MDA-MB-231 and liver cancer cells HepG2 were detected by MTT method. Notably, compound 13d exhibited an IC₅₀ value of 8.97 ± 0.22 µM against HepG2 cells and showed selectivity towards human normal hepatocyte (LX-2, IC₅₀ = 49.88 ± 3.39 µM). In addition, morphological changes, cell growth curve and colony formation indicated that compound 13d could significantly inhibit proliferation of HepG2 cells. Furthermore, Hoechst 33342 staining and flow cytometry confirmed that compound 13d induced apoptosis in HepG2 cells, and activation of apoptosis markers caspase 3 and PARP was further observed via western blot analysis. Our study indicates that compound 13d may be a potent lead candidate for cancer therapy against liver cancer.

Diabetes mellitus, especially type 2 diabetes, is a metabolic disease that progresses with time and requires efficient management to avoid long-term problems. One promising approach to target Diabetes mellitus is to inhibit α-glucosidase to control postprandial hyperglycemia. In this work, new quinoline-benzoylhydrazine (7a–m) are designed, synthesized, and evaluated as possible α-glucosidase inhibitors. The Vilsmeier–Haack reaction was used in a multi-step process to synthesize the derivatives, and their inhibitory properties were evaluated. Kinetic analyses of the potent analog were conducted. Critical hydrogen bonding and π-π stacking interactions indicate the substantial binding affinity of the potent analog into the enzyme’s active site, as demonstrated by molecular docking and molecular mechanics with generalised born and surface area solvation (MM/GBSA) simulations. Furthermore, molecular dynamics simulations of the most potent analogs provided insights into their stability and interaction dynamics with the enzyme. These findings suggest that the designed derivatives are promising leads for developing novel α-glucosidase inhibitors to manage type 2 diabetes effectively.