MedChemComm最新文献

The epidermal growth factor receptor (EGFR) family comprises four distinct members with similar framework characteristics: EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). EGFR plays a pivotal role in cellular signaling pathways that regulate key pathological processes, including apoptosis, uncontrolled cell proliferation, metastasis, and angiogenesis. However, clinically used EGFRs such as apatinib, selumetinib, gefitinib, vandetanib, and erlotinib are not selective, thereby resulting in troublesome side effects. Drug obstruction, alteration, and specificity represent a few of the primary obstacles in the development of unique key compounds as EGFR inhibitors, stimulating medicinal chemists to discover innovative chemotypes. The development of drugs that block specific stages of cancerous cells, such as EGFR, is one of the main goals of many cancer treatments, including breast and lung tumors. Thus, the current study endeavored to summarize the numerous recent advancements (2016–2024) in the research and development of diverse epidermal growth factor receptor (EGFR) inhibitors, focusing on pyrrole, indole, pyrimidine, oxadiazole, isoxazole, and other structural classes. Preclinical, clinical, structure–activity relationships (SAR) with mechanism-based and in silico research, and other relevant data are compiled to offer directions for the scientific discovery of novel EGFR inhibitors with conceivable uses in therapy. The research trajectory of this entire field will provide incessant opportunities for the discovery of novel drug molecules with improved efficacy and selectivity.

Conopressins are single disulfide conopeptides with a close sequence similarity to vasopressin and oxytocin, exhibiting grooming and scratching effects in rodents. Here, we have investigated the impact of stereochemistry on the conserved arginine residue at position 4 and the truncation (Tr-Mo976 and Tr-Mo977) on the structure and activity of conopressins. 3D structures determined by solution NMR revealed distinct structural features for Mo1033 and ^DR4-Mo1033. Molecular dynamics studies of the conopressins with oxytocin and V2 receptor complexes revealed that both Tr-Mo976 and Tr-Mo977 showed robust interactions with the OT receptor and reduced interactions with the V2 receptor. In addition, conopressins exhibited anti-inflammatory and antioxidant potential in LPS-stimulated macrophages. Behavioural studies in mice demonstrated high grooming and scratching behaviour for Tr-Mo976 and reduced locomotory activity with Tr-Mo977. To this end, results suggest that both the truncation of the tail region and the nature of residue 8 play an essential role in altering the activity of conopressins.

Depression is a complex mental disorder, and consequently, the successful treatment of the depressive disorder remains challenging. The available medications often show limitations in terms of both safety and efficacy. In this case, the presence of the prenyl motif in pharmaceutical compounds has resulted in a broad spectrum of biological activities. Various studies have highlighted that the potent antidepressant activity of many natural compounds is associated with the presence of the prenyl motif. Thus, some studies have attempted to prepare prenyl fragment derivatives with the aim of enhancing their hydrophobicity and developing promising antidepressant compounds. Prenyl motif-containing compounds exhibit antidepressant action via multiple mechanisms, including selective serotonin/norepinephrine reuptake inhibition, blocking of NMDA receptors, 5-HT₆ antagonism, TREK-1 inhibition, MAO-A inhibition, and anti-inflammatory and antioxidant properties. This review presents synthetic derivatives of xanthones, flavonoids, and chalcones bearing prenyl groups. It also covers polyprenylated benzoyl phloroglucinols/acylphloroglucinols, naphthoquinones, volatile oils, tricyclic products, and steroidal saponins containing prenyl motifs. This study aims to further guide and support medicinal chemists in directing the synthesis of more potent compounds possessing prenyl fragments as antidepressants, thus advancing treatment options for depression.

Traditional ways of formulating azithromycin are characterized by low oral bioavailability. Therefore, the development of new formulations to enhance drug bioavailability is crucial. The current study aims to evaluate the in vitro kinetics and sustained release of azithromycin (AZM) from a newly designed CS/CeO₂@ZnCr LDO glycerosome incorporating chitosan, soy lecithin, and glycerol. Various analytical techniques, including Fourier transform infrared spectroscopy (FTIR), Brunauer–Emmett–Teller (BET) analysis, scanning electron microscopy (SEM), X-ray diffraction (XRD), and zeta potential measurements, were employed for analysis. After two hours, 70.9% of the drug was released from CS/CeO₂@ZnCr LDO glycerosomes at pH 7.4 (PBS), which can be attributed to their good swelling properties at various pH levels, temperatures, and time intervals. Kinetic analysis revealed that the Peppas–Sahlin model provided the best fit, with a release exponent (m) of 0.805 at pH 7.4, indicating an anomalous (non-Fickian) drug release mechanism. The Peppas–Sahlin and Weibull models were identified as the best fits for the sustained release data. Cytotoxicity assessments revealed that at a lower concentration of 2.5 μM, chitosan/CeO₂@ZnCr LDO glycerosomes/AZM exhibited no toxicity to the cells over 24 hours, suggesting that this concentration is suitable for further research. Furthermore, at a concentration of 6 mg ml⁻¹, chitosan/CeO₂@ZnCr LDO demonstrated enhanced efficiency against Gram-negative bacteria compared to Gram-positive bacteria when compared to CeO₂@ZnCr LDO. This study highlights the potential of this system to improve the therapeutic efficacy of azithromycin, particularly in the treatment of complex infections, while also offering a straightforward and scalable formulation approach for clinical translation.

A series of melatonin biphenyl-linked conjugates was designed and synthesized using a simple, cost-effective, and environmentally friendly method. All the new compounds were evaluated for their cytotoxic or cytostatic activity against SW480 human colorectal adenocarcinoma cells. Screening at 100 μM revealed that most compounds exhibited high activity (≥60% inhibition), with compounds 3b, 3h, 4f, 4g, and 4i–l also demonstrating subtle lethality. Based on these initial results, a subset of the most active hybrids was selected for further in-depth evaluation to calculate three key parameters of cell viability: GI₅₀, TGI, and LC₅₀ values. The results showed that most compounds, except 3c and 4d, significantly outperformed the parental compound (2 and melatonin) in inhibiting cancer cell proliferation, highlighting the efficacy of hybridization in improving cytotoxic potential. Besides, it is noticeable that hybrids 4f–l exhibited superior activity compared to 5-FU, as evidenced by lower GI₅₀ values. Although hybrids 4f and 4g seemed to exert the greatest activity as demonstrated in the LC₅₀ values (70.89 ± 11.72 μM and 68.03 ± 0.46 μM, respectively), we observed that only hybrids 4j and 4l showed significant selectivity, as revealed by higher GI₅₀ concentrations over non-malignant cells (NCM460). The observed total growth inhibition and lack of LC₅₀ values in 4j and 4l suggest their potential for a cytostatic effect. Lastly, theoretical evaluations of drug-likeness, pharmacokinetic behaviour, and toxicological parameters suggest that the most promising hybrids, compounds 4j and 4l, exhibit strong potential for advancement into preclinical studies. Our findings highlight the effectiveness of a novel melatonin biphenyl-linked scaffold, with 4j and 4l structures in particular serving as prototypes for future innovative adjuvant drugs.

Microwave-assisted synthesis of new pyrrole and indole derivatives as tubulin assembly inhibitors was performed with remarkably improved yields and short reaction times. In designing the new inhibitors, aryl ring reversal and conjunctive approach notions were applied. (4-(4-Methoxyphenyl)-1-(pyridin-2-yl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl) methanone (4) inhibited [³H] colchicine binding by 78% and MCF-7 breast cancer cell growth with an IC₅₀ of 9.6 nM. Compound 4 also inhibited the growth of HCT116, BX-PC3 and Jurkat cancer cells with IC₅₀ values of 18, 17 and 41 nM, respectively, and altered the morphology of treated spheroids in both the BX-PC3 and HCT116 cell lines.

Metal chelators belonging to the di-pyridyl-thiosemicarbazone (DpTs) class have shown great promise as adjuvant therapeutics for treating cancer, with DpC and Dp44mT emerging as the lead candidates. Despite their efficacy, these molecules also induce various undesirable side effects due to insufficient cancer cell targeting, highlighting the need to improve their selectivity. Here, we present a first generation of DpT–antibody conjugates. To this end, we developed a facile synthesis to functionalize DpTs strategically with click-able azido linkers. Moreover, selective side-chain modification of the clinical antibody trastuzumab (Tras) with a complementary bis-alkyne moiety is described. Using this new chemistry, we conjugated four different azido DpTs to trastuzumab via a combination of oxidation-controlled quinone (SPOCQ) and strain-promoted alkyne–azide click (SPAAC) chemistry. We evaluated the antiproliferative activity of the resulting novel antibody–drug conjugates (ADCs) against MCF-7 and SK-BR-3 cell lines. Linker positioning on the DpT scaffold significantly influences the cytotoxicity of the conjugates. For instance, conjugating Tras at the ortho position on the Dp44mT scaffold is more efficacious than conjugating at the para position with IC₅₀ values of 25.7 ± 5.5 nM and 103.5 ± 2.0 nM, respectively, against MCF-7 cells. Furthermore, we observe intriguing cell line-dependent activity of the ADCs with increased selectivity towards MCF-7 cells, providing novel insights into the cytotoxic activity of DpTs and their antibody conjugates.

The unanticipated finding of cisplatin's anticancer properties prompted extensive investigations into different platinum-containing complexes as anticancer agents. However, the side effects and resilience of cancerous cells to platinum complexes triggered investigations on non-platinum anticancer complexes. As a result, several non-platinum complexes have been developed. Among these, the anticancer potential of cobalt complexes has been recognized over the past few decades. Inorganic medicinal chemists are fascinated by cobalt complexes, as these complexes interact with cellular proteins and macromolecules, causing cellular disruption and stopping the division, growth and multiplication of cancer cells. Owing to the increasing interest of researchers in the development of anticancer cobalt complexes, this paper critically reviews the developments in the design and development of these complexes. The results of the in vitro and in vivo investigations of anticancer profiles of cobalt complexes with ligands such as Schiff bases, quinolines, carbonyl groups, polypyridyl ligands, macrocycles, thiosemicarbazones, active pharmaceuticals, natural products, etc. are reviewed. Importantly, the intervention of nanotechnological approaches in amplifying the therapeutic properties of anticancer cobalt complexes is discussed. Besides, the modes of action of anticancer cobalt complexes are highlighted. Moreover, pharmacologically significant cobalt complexes with equal or better anticancer effects than that of standard anticancer agents are identified. Finally, the existing challenges and future perspectives in research on the design and development of anticancer cobalt complexes are discussed.

Mangiferin with a xanthone scaffold exhibited potent anti-obesity activities and thus has attracted interest. However, some shortcomings, including limited solubility and moderate potency, restrict its application. To develop novel and efficient anti-obesity agents, a series of mangiferin (MGF) amino acid derivatives were synthesized, optimized and evaluated for anti-obesity activities in vitro and in vivo. Among these derivatives, G1 was identified to be a promising compound. G1 showed better liposolubility compared to MGF. In 3T3-L1 preadipocytes, G1 significantly inhibited cell differentiation and reduced fat accumulation by increasing inhibitory activity on fatty acid synthase, and triggering G0/G1 phase cell cycle arrest and production of intracellular reactive oxygen species. The intraperitoneal administration of G1 (30, 60 mg kg⁻¹/2 days) significantly inhibited body, liver and fat tissue weight gain, reduced lipid dysfunction, and ameliorated pathological characteristics in high-fat diet induced C57BL/6J obese mice. These results suggest that compound G1 may warrant further investigation as a promising anti-obesity agent for the treatment of human obesity.

The rapid emergence of antibiotic resistance in bacteria has created an alarming situation in public health, which remains a major concern worldwide. In addition, the biofilm-forming ability of bacteria has further complicated the situation in the current scenario. To address these global clinical threats, small molecular mimics of antimicrobial peptides (AMPs) have emerged as a promising class of antibacterial agents. These molecules primarily kill bacteria by targeting their membranes, making it difficult for bacteria to develop resistance against them. Some of these classes of molecules have already been reported as potent antibiofilm agents and have demonstrated promising in vivo efficacy. In this review, we aim to provide an overview of this class of molecules with a focus on recent developments in the field. Different classes of small molecular AMP mimics are discussed with an emphasis on design rationale and the structure–activity-relationship (SAR) facet. The role of different parameters (such as hydrophobicity, charge, structural flexibility/rigidity, and spatial distribution of hydrophobicity) that control their physico-chemical property and thereby the antibacterial activity and toxicity is illustrated. Moreover, the antibiofilm ability and in vivo efficacy of this class of molecules are described to elucidate the possibility of being developed as future antibacterial drugs. Finally, the challenges associated with this class of molecules for their clinical translation as antibacterial therapy are discussed along with future perspectives for advancing the field.