Future medicinal chemistry最新文献

Introduction: Malaria causes major mortality, with the downward trend in the number of cases and deaths seemingly stalled. In 2023, 95% of global malaria deaths were reported in the World Health Organization (WHO) African region, with children under the age of 5 years being the most affected. Artemisinin-combination therapies (ACTs), the currently recommended first-line treatments, are threatened by resistance, which has so far been reported in Africa and Southeast Asia. Thus, new drugs are needed.

Areas covered: In this review, we discuss the two main antimalarial drug discovery paradigms (phenotypic- and target-based drug discovery approaches) and highlight their impact in antimalarial drug development, as judged by the clinical candidates these two drug development philosophies have delivered in the last two decades. We also highlight the geographical imbalance in contributions to research and development (R&D) efforts that led to the development of these clinical candidates.

Expert opinion/commentary: While phenotypic-based drug discovery outperformed the target-based approach, we propose some strategies to improve chances of success in the latter strategy. Furthermore, although antimalarial drug discovery and development has seen an encouraging shift toward more collaborations among industry, academia, and product development partners, R&D in this space remains concentrated in the global north.

Aim: Urease is essential to Helicobacter pylori metabolism and plays role in stomach cancer, gastritis, peptic ulcer, hepatic coma, urinary tract infection, liver encephalopathy, and pyelonephritis. Therefore, inhibition of urease is an appealing approach to treat bacterial infections.

Materials and methods: The present work describes the synthesis of a series of ten new bioactive isatin-thiazole conjugates (5a-j). The target adducts were characterized using fourier transform infrared (FT-IR), ¹H- and ¹³C- nuclear magnetic resonance imaging (NMR) spectroscopy. The compounds were obtained using a multistep strategy that included nitration, alkylation, condensation and cyclization sequence. Subsequently, these compounds were screened for their urease inhibition potential.

Results and conclusion: All the compounds showed better inhibitory potential than the positive control, thiourea with IC₅₀ ranging from 0.44 to 8.70 µM. However, compound 5j exhibited an excellent non-competitive urease inhibitory effect with an IC₅₀ value of 0.44 ± 0.23 µM. Apart from in vitro investigation, the molecular docking revealed a strong affinity of 5j within the active site of urease exhibiting a binding energy of -7.9 kcal/mol. Succinctly, the lead inhibitor 5j exhibited noteworthy IC₅₀ and effective binding free energy which emphasizes its strong binding potential.  .

Aim: New pyrazole and 1,3-thiazolyl-pyrazole derivatives were prepared in high yields.

Materials and methods: The structures of the desired compounds were determined and characterized using ¹H NMR, ¹³C NMR, FT-IR, and ESI-MS spectroscopy. The compounds were screened for anticancer activity against human epithelial colorectal adenocarcinoma (Caco-2). The anticancer mechanisms were investigated with apoptosis studies and molecular docking. Using Auto Dock vina, the effective chemicals were docked into the human epidermal growth factor receptor (BAX, caspase-3, and TNF-α) to investigate anticancer activity.

Results: Among the tested compounds, pyrazole compounds 13 and 8 exhibited the highest result effect against the tested Caco-2 cell line (IC₅₀ = 2.12 ± 55.17 μM) and (IC₅₀ = 2.44 ± 59.92 μM), respectively. While compounds 5b and 15c displayed the moderate result effect against the tested Caco2cell line (IC₅₀ = 2.33 ± 20.4 μM) and (IC₅₀ = 1.54 ± 9.65 μM) respectively. Molecular docking analysis revealed that compounds 8, 5b, 13, and 15c exhibit strong binding affinities to BAX, with binding energies of -8.20, -7.90, -7.50, and -7.70 kcal/mol and show significant binding affinities to caspase-3, with binding energies of -6.80, -7.00, -7.30, and -7.60 kcal/mol, respectively. Also, compounds 8, 5b, 13, and 15c display strong binding affinities to TNF-α, with binding energies of -7.60, -7.10, -6.50, and -6.80 kcal/mol, respectively.

Conclusion: The activity of synthesized 1 H-substituted carbothioamide pyrazole derivatives was increased when added to thiazole with different electron-withdrawing groups.

Aims: To design, synthesize, and characterize N-(4-bromophenyl)-2-(substituted fluorobenzylidene)hydrazine-1-carbothioamides (II-IV) and evaluate their in vitro cytotoxicity against DLD-1 and MDA-MB-231 cells, supported by molecular docking.

Materials & methods: Compounds were obtained by condensations of substituted fluorobenzaldehydes with N-(4-bromophenyl)hydrazinecarbothioamide and characterized by NMR, FTIR, and MS. DLD-1 and MDA-MB-231 cells were exposed to 50-1600 µg/mL for 24 h; viability was measured using a commercial colorimetric assay. Statistics used one-way ANOVA with post hoc tests. Blind docking was performed with CB-Dock2 and interactions inspected in Discovery Studio.

Results: All compounds decreased viability in a concentration-dependent manner. In MDA-MB-231, Compounds I, II, and IV showed significant effects (ANOVA p < 0.001). In DLD-1, Compound IV reached p ≤ 0.01 and Compounds I-II p < 0.001; the IC₅₀ of Compound I in DLD-1 was 1383.2 µg/mL. Docking suggested favorable binding poses stabilized by hydrogen bonding and hydrophobic/halogen interactions at key residues.

Conclusions: The 4-bromophenyl thiosemicarbazone/Schiff-base scaffold exhibits measurable antiproliferative activity with substitution-dependent trends supported by docking. These findings warrant structure optimization to enhance potency and selectivity and motivate follow-up mechanistic assays. (Not a clinical trial; CONSORT not applicable.).

Purpose of objective: This study aims to develop novel spiro-pyrrolizidine-benzyloxy hybrids (RP₁, RP₂, and RP₃) to reduce the dosage and mitigate the side effects of doxorubicin (DOX) while harnessing potential synergistic effects for enhanced anticancer efficacy.

Methods: Spiro-pyrrolizidine-benzyloxy hybrids (RP₁, RP₂, and RP₃) were synthesized using isatin, L-proline, and sub-chalcone. The anticancer potential of these compounds was evaluated against MDA-MB-231 breast cancer cells. Based on superior efficacy, RP₁ was selected and compounded with doxorubicin in different ratios. The anticancer efficacy of these compounded formulations was assessed through cell viability assays and IC50 values.

Results: Among the synthesized hybrids, RP₁ exhibited the highest anticancer efficacy against MDA-MB-231 cells. When RP1 was combined with doxorubicin, the combination showed reduced cell viability, with the most effective ratio being 23.50 µM (20:80) (RP₁: dox), followed by 11.22 µM (50:50) and 8.82 µM (80:20). The compounded formulation resulted in a lower IC50 value compared to doxorubicin alone, indicating enhanced efficacy.

Conclusions: Compounding RP₁ with doxorubicin effectively enhances anticancer activity while potentially reducing the side effects associated with doxorubicin's quinone-hydroquinone moiety. The optimized formulation (80:20) presents a promising approach for improving breast cancer treatment outcomes.

Pyruvate kinase M2 (PKM2) is a central regulator of glycolysis and anabolic metabolism, playing a pivotal role in cancer cell proliferation. Its multifunctional nature and involvement in various disease pathways make it an attractive therapeutic target, especially in oncology and inflammation. This review summarizes research over the past five years on small molecule PKM2 inhibitors. Activators of PKM2 promote the tetrameric form of PKM2, enhancing oxidative phosphorylation and reversing the Warburg effect. In contrast, inhibitors like micheliolide (MCL) and isoselenazolium compounds disrupt PKM2's non-metabolic roles, inducing tumor cell death. Literature was selected through focused searches on PKM2-targeted therapies in cancer, inflammation, and neurodegeneration, with attention to recent advances in structural biology, computational modeling, and high-throughput screening. PKM2 modulators show promise across a range of diseases beyond cancer, including inflammatory and neurodegenerative conditions. However, challenges in isoform selectivity, toxicity, and clinical translation persist. Although, no PKM2 inhibitors have entered and succeeded in clinical trials, continued research and technological advances are essential to unlock PKM2's full therapeutic potential and guide its development into safe, effective clinical treatments.

This review explores the use of metallodrugs, compounds formed by coordinating metals with organic molecules, as a promising strategy to enhance therapeutic efficacy and address the limitations of conventional drugs. Essential metals, such as copper and zinc, play critical biological roles and can impart unique pharmacological properties, including improved solubility, bioactivity, and selectivity, while potentially reducing toxicity. Despite these advantages, modeling and characterizing metallodrugs remains challenging due to their variable oxidation states and diverse coordination geometries. Advanced techniques, such as NMR spectroscopy, X-ray crystallography, and mass spectrometry, are crucial for elucidating their structure and function. The future development of these drugs relies on refining these methodologies and implementing innovative delivery strategies, like metal-organic frameworks (MOFs), to create safer and more effective therapies. By strategically designing metal-ligand interactions, metallodrugs can achieve targeted bioactivity and overcome resistance mechanisms, positioning them as next-generation therapeutics with the potential to transform treatments in oncology, infectious diseases, and beyond.

Aims: This study involves the synthesis of indolophenyl carboxamides, computational analysis, and assessing the compounds against Plasmodium falciparum strains.

Materials and methods: Indolophenyl carboxamides were synthesized and characterized using ¹H NMR and ¹³C NMR, and HRMS techniques, and were evaluated against the P. falciparum 3D7 and C580Y strains by using the SYBR Green I assay.

Results and conclusion: Compounds 1, 7, 8, and 9 showed potent antimalarial activity against Pf3D7 and Pf C580Y with IC₅₀ values of 8.9 and 3.4 µM, 5.5 and 2.2 µM, 10.1 and 14.0 µM, and 12.2 and 28.6 µM, respectively, and were nontoxic to human cells. Further, in silico studies confirmed Plasmodium dihydrofolate reductase as the target of indolophenyl carboxamides. This study identifies indolophenyl carboxamides, including bisindole, as promising new antimalarial agents effective against sensitive and drug-resistant P. falciparum.

MMP-2 is crucial for ECM remodeling and embryonic development. MMP-2 is a key biomolecular target for its strong association with cancer progression, metastasis, and angiogenesis. Again, the implication of MMP-2 in other diseases is well-established. Though several MMPIs failed after extensive clinical studies due to a lack of selectivity, poor pharmacokinetics, and dose-related toxicities, there is still a huge opportunity to develop specific MMP-2 inhibitors to battle against such life-threatening diseases as cardiovascular diseases, diabetes, renal diseases, and inflammatory diseases. Here, the development of small-molecule MMP-2 inhibitors for the last five years, comprising various ZBGs and diverse scaffolds, as well as their structural information along with their in-depth biological implications in cancers and other diseases, has been discussed in detail. This study may reinforce the importance of potential and selective MMP-2 inhibition as a therapeutic approach, paving the way for future research into optimizing small-molecule MMP-2 inhibitors for clinical applications. As the development of these MMP-2 inhibitors advances, further in vivo studies and structure-activity relationship optimizations will be essential to translate these promising results into viable therapeutic options for several cancers and other life-threatening diseases.

Introduction: Cancer is one of the predominant causes of mortality globally. Radiation, surgery, and chemotherapy are currently available methods for treating cancer. Each of these approaches has known adverse effects. Due to their better efficacy and safety over traditional chemotherapy drugs, targeted therapeutic medicines are quickly becoming standard cancer treatments.

Areas covered: Small molecules have several advantages, such as being able to be given orally and having the capacity to pass through cell membranes and enter intracellular spaces. This review is going to focus on small molecules as anticancer scaffolds and researchers will be able to design new antineoplastic compounds in the future on the basis of the thoroughly discussed SAR investigation, preclinical data, clinical outcomes, and FDA approved molecules.

Expert opinion: Since there is currently no cure for most forms of disseminated cancer, the development of novel active chemotherapeutic drugs is essential. Small molecules are interesting drug candidates as they are able to target important molecular pathways with selectivity. An in-depth analysis of the SAR study and the available preclinical and clinical data can greatly assist in the development of the next generation of anticancer drugs that would be more potent, selective, and would interfere with fewer side effects.