Medicinal Chemistry Research最新文献

A series of tetrahydrobenzo [4, 5] thieno [2, 3-d] pyrimidinone derivatives 3a–j and 4–6 was synthesized, and tested for their inhibitory activity against E. coli DNA gyrase in a supercoiling assay. The results showed that the five most promising compounds, 3d, 3g, 3h, 3i and 3j were the most potent, therefore, they were selected for investigating their inhibitory activity against E. coli topoisomerase IV, S. aureus DNA gyrase, and S. aureus topoisomerase IV. The results revealed that compound 3j was a more effective inhibitor of E. coli topoisomerase IV, S. aureus DNA gyrase and S. aureus topoisomerase IV, respectively. The molecular docking study of compound 3j has revealed that it binds effectively in the active sites of E. coli DNA gyrase B and E. coli DNA topoisomerase. The hybrid 3j particularly showed promise as a scaffold for designing and developing novel therapeutic antibacterial candidates.

Tetralin is an ortho-fused bicyclic hydrocarbon notable for its odour of a mixture of benzene and menthol and high boiling point. Its low vapor pressure has limited its study by far-infrared spectroscopy but vibrational data have been obtained through alternative methods such as single vibronic level fluorescence (SVLF) and high-temperature vapor-phase Raman spectra. Tetralin is of more than chemical interest because it is part of several biologically active compounds. Interestingly, tetralin is a structural element of the anthracycline antibiotics that are clinically applied in cancer chemotherapy owing to their DNA-intercalating activity. The tetralin ring is crucial in sertraline, an antidepressant, and other clinically relevant compounds, including antifungal, anti-Parkinsonian, and anti-inflammatory activity. A comprehensive overview of tetralin derivatives with their diverse biological activities and therapeutic potentials has been discussed in the review. It also encompasses the synthetic methodology for the synthesis of tetralin and its derivatives including hydrogenation, and cyclization through metal catalysts, and visible light. In addition, a green chemical synthetic technique such as supercritical fluid technology was discussed, which improves the production of tetralin. Apart from that, metabolic pathways and catabolism of tetralin in biological systems and drug delivery systems of tetralin have been discussed. The review underlines the importance of tetralin derivatives in medicinal chemistry and has future developmental potential in therapeutic applications.

Virulence is an organism’s ability to infect the host and cause disease, and this ability is determined by the presence of virulence factors. The “do not kill, neutralize” strategy used by antivirulence therapies is a novel approach to managing the increasing drug resistance. In this respect, type IV pilus is one druggable target among many virulence factors. The type IV pili (T4P) assembly systems with adaptable and flexible filaments are utilized by numerous pathogens for infection. The current work focuses on druggable targets of T4aP with specific emphasis on Pseudomonas aeruginosa, Neisseria meningitidis, and Neisseria gonorrhoeae. Additionally, available information on potential inhibitor molecules that attenuate T4P activities or impair pilus function and/or assembly in different pathogens is summarized. The structural organization of T4aP suggests that ATPases, pilins, tip-associated adhesins, and peptidases could be considered potential target sites. As the number of high-resolution structures of different T4P systems and the computational power to model T4P machineries increase, the pace in the identification of novel molecules and targets to attenuate the activities of T4P will accelerate. Artificial intelligence, which has already penetrated into our daily lives, will definitely have a prominent role in providing a framework for progress in this area.

In this study, we designed and synthesized 41 quinazoline derivatives with different base amine termini. Compound 15n showed the best antiproliferation activity against A549 cells with IC₅₀ value of 1.91 μM in four cancer cell lines (MGC-803, PC-3, A549, and Eca-109). In colony, scratch, and apoptosis experiments, compound 15n inhibited proliferation, migration, and apoptosis of A549 cells in a concentration-dependent manner and blocked the cell cycle in the G0/G1 phase. Overall, our study suggests that compound 15n has potential as a lead compound for the development of antitumor drugs.

A series of new oxepinyl triazoles were synthesized using labdane diterpene sclareol as a template. The synthesis process involved several steps including oxidation, oxetane ring opening, deacetylation, tosylation, and azidation followed by Huisgen’s 1,3-dipolar cycloaddition reaction with different alkynes. The newly synthesized compounds were confirmed using ¹H NMR and ¹³C NMR. These novel drimane oxepinyl triazoles derived from labdane diterpene sclareol were evaluated for their antiproliferative efficacy in colon (HCT-116), breast (MCF-7), and lung (A-549) cancer cell lines. Compound 14m demonstrated significant cytotoxic effects in all tested cell lines with an IC₅₀ of 16 µM. Initial investigations suggested that the compound induced apoptosis and inhibited cancer cell proliferation, indicating the potential of drimane oxepinyl triazoles as promising therapeutic agents for various cancers.

The roots of Litsea cubeba (Lour.) Pers have been used for the treatment of rheumatism. We previously extracted and isolated the natural product dibenzylbutane lignan LCA with anti-inflammatory activity. In the current study, using LCA as the lead compound, two series of LCA derivatives with an imide structure and butadiene structure were designed and synthesized. Among them, compounds 10c and 16a showed stronger inhibitory effects on LPS-induced NO and ROS production in RAW264.7 cells. Further study showed that compound 16a not only reduced the levels of inflammatory cytokines, including IL-6, TNF-α, and IL-1β, but it also significantly reduced the expression of iNOS and COX-2. Preliminary mechanism of action studies suggested that 16a exerts anti-inflammatory effects by inhibiting the NF-κB signaling pathway. Overall, our results suggest that compound 16a may be used as a promising anti-inflammatory drug to enrich the compound library. Further study into compound 16a could provide research ideas and methods for developing anti-inflammatory drugs.

Resistance to β-lactam antibiotics caused by β-lactamases such as New-Delhi lactamase (NDM-1) has become one of the major challenges in the current antimicrobial therapy. Pyridine-2,6-dicarboxylic acid (DPA) derivatives have been demonstrated to inhibit NDM-1 in a due to the interactions with Zn ion and amino acid residues of the enzyme’s active site. In this study, a series of new 4-substituted DPA derivatives was synthesized. The SAR study has proven that the presence of a substituent at the 4-position of pyridine-2,6-dicarboxylic acid had a certain impact on the NDM-1 inhibitory. Some representatives, e.g., 4e exhibited IC₅₀ values against NDM-1 close to the previously reported hit-compound 4-(3-aminophenyl)pyridine-2,6-dicarboxylic acid. The microdilution broth test confirmed an ability of derivative 4e to increase susceptibility of NDM-1-producing E. coli strain and did not demonstrate cytotoxicity to eukaryotic cells. However, NDM-1 inhibition by 4-substituted derivatives dramatically dropped when Zn²⁺ was added. We observed a strong complexation of 4-modified derivatives with Zn²⁺ similar to unsubstituted pyridine-2,6-dicarboxylic acid. Taken together, a complexation mode of NDM-1 inhibition leading to potential off-target action on other metalloenzymes and low efficiency of structure optimization make DPA derivatives an unproductive scaffold for future development of clinically relevant metallo-β-lactamase inhibitors.

Harmine is a naturally occurring heterocyclic compound belonging to the β-carboline alkaloid class, found in various plants, some animals, insects, and marine organisms. Harmine and its derivatives possess significant pharmacological activities, particularly anticancer properties, making them promising candidates for cancer therapy. Despite its efficacy, harmine has adverse effects, including neurotoxicity related to the methoxy group at position 7, which limits its clinical application. To address these limitations, researchers have focused on developing new and more potent derivatives with minimal side effects to improve the therapeutic index and clinical applications of harmine. Therefore, several studies have investigated the anticancer activity of these molecules, revealing their tremendous ability to regulate various cellular mechanisms involved in cell malignancy, including pathways related to cell cycle regulation, apoptosis, and metastasis. This article reviews the most relevant studies conducted in recent years, highlighting the evidence for the anticancer activity of harmine and its derivatives in various cancer cell lines. It also focuses on the mechanisms of action in both in vitro and in vivo models and discusses the structure-activity relationship of the most effective compounds, providing insights into future drug development strategies.

Tetrahydro-β-carbolines are medicinal important class of compounds have their place in indole family. N-benzylation variations at indole of Tetrahydro-β-Carboline’s needs to explored of its pharmacological activities. Seventeen N-11-benzylic- β-carboline derivatives were synthesized from 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetaldehyde and 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine (N-alkylated) via Pictet–Spengler reaction and Keto reduction using LiCl/NaBH₄, including eleven N-substituted and six Keto reduced β-carboline derivatives. Antimalarial activities of these analogs were studied on 3D7 and C580Y parasite strains.

American trypanosomiasis and leishmaniasis are worldwide health problems that warrant attention given the current ineffective treatment options. In this study, 6-ester-, and 6-benzamide- benzofuroxan-1-N-oxide derivatives were evaluated against trypomastigotes of the NINOA of Trypanosoma cruzi (T. cruzi), and promastigotes of QEPS strain of Leisnmania mexicana (L. mexicana). Compounds BFX-9, and BFX-10 had the best trypanocidal activity with values of half-maximal inhibitory concentration (IC₅₀) of 16.25, and 0.5 µM, respectively, over 9-fold more active than both benznidazole and nifurtimox. Also, BFX-10 had the best selectivity index (SI) value of 77.16 toward trypomastigotes of T. cruzi over macrophages J774.2. Compounds BFX-3, BFX-5, and BFX-8 had the best leishmanicidal activity, better than glucantime, and miltefosine, with IC₅₀ values 9.75, 7.03, and 9.57 µM, and SI values of 3.91, 3.92, and 4.64, respectively, toward L. mexicana promastigotes over macrophages. This study shows that new modifications at 6-position on the benzofuroxan scaffold allowed obtain potent anti-Trypanosoma cruzi and anti-leishmania agents.