Aug 2026· Bioorganic & Medicinal Chemistry Letters· Vol 141, pp.
130756
· 0 citations· 18 references
Medicine
TL;DR
In silico ADME analysis indicated that both lead compounds possess favourable drug-like properties, with no Lipinski's rule-of-five violations, balanced lipophilicity, and acceptable predicted oral absorption, supporting their pharmacokinetic potential.
Abstract
The immune checkpoint enzyme CD73 plays a crucial role in the adenosine (ADO) metabolic pathway by catalyzing the conversion of AMP to adenosine. Dysregulated CD73 activity elevates extracellular ADO in the tumor microenvironment, driving immunosuppression and tumor immune evasion, highlighting CD73 as a key immunotherapeutic target. In this study, we report the design and synthesis of a novel series of salicylamido sulfonamide-based small-molecule CD73 inhibitors. The in vitro CD73 inhibitory assay reveals that SA-41 and SA-26 exhibited potent activity with IC50 values of 2.83 ± 0.45 μM and 2.96 ± 0.46 μM, respectively. Molecular docking and dynamic simulations revealed that SA-26 maintained stable interactions with CD73 throughout a 100-ns simulation with no significant deviation. Furthermore, in silico ADME analysis indicated that both lead compounds possess favourable drug-like properties, with no Lipinski's rule-of-five violations, balanced lipophilicity, and acceptable predicted oral absorption, supporting their pharmacokinetic potential. These findings highlight SA-26 and SA-41 as promising candidates for further development as non- nucleotide-based small-molecule CD73 inhibitors.
A series of novel 1,2,4-triazole-azetidin-2-one hybrids (A1-A12) were designed and synthesised as potential anti-tubercular agents. The compounds were synthesised via Schiff base formation followed by cyclocondensation reactions. The compounds were studied as anti-tubercular agents against polyphosphate kinase 2 (PPK2), an enzyme involved in nucleotide regulation in Mycobacterium tuberculosis. A three-dimensional model of PPK2 was generated and examined by molecular dynamics studies. Docking studies indicated favourable interactions of some compounds with amino acid residues ASN131, GLU136, LYS75 and ARG127 in the active site of PPK2, supporting their possible role as PPK2 inhibitors. ADMET simulation analysis revealed favourable physico-chemical and pharmacokinetic parameters, satisfying the criteria for oral drug-likeness. The anti-tubercular activity of compounds A1-A12 was evaluated against M. tuberculosis H37Rv using the minimum inhibitory concentration (MIC) method. Compounds A11 and A12 exhibited the highest activity with MIC values below 7.81 μg/mL, while the remaining derivatives showed moderate to weak activity. Cytotoxicity studies on Vero cells demonstrated concentration-dependent effects, and IC50 values indicated acceptable selectivity for compounds A1 and A12. Acute oral toxicity studies in mice established an LD50 value of 300 mg/kg. Histopathological examination of major organs revealed no significant structural changes at tolerated doses.
Triveni Singirisetty, Vijaya Bhaskar Kuruba, Azger Dusthackeer Vijayan Nynar et al.· Asian Journal of Chemistry· 0 citations
The indoleamine 2,3-dioxygenase 1 (IDO1) enzyme promotes an immunosuppressive microenvironment and disrupts natural antitumor immune response in cancer cells. IDO1 inhibition has been a target of multiple cancer immunotherapy efforts and is of interest to autoimmune and neurodegenerative disease therapeutic areas. While the first-generation holo-IDO1 inhibitor, epacadostat, did not demonstrate sufficient response in the phase III ECHO-301 trial, multiple next-generation inhibitors and combination therapy clinical trials are ongoing. Herein, we describe our IDO1 inhibitor discovery and optimization effort, in which the lipophilic ligand efficiency index was used to track and guide drug-likeness, minimize entropic penalty, and deliver novel, potent, selective, and orally bioavailable apo-IDO1 inhibitors. Compounds in this class have the potential for an improved pharmacodynamic response and thus are potentially attractive clinical candidates. Our lead molecules are achiral and can be easily synthesized on a large scale in several synthetic steps.
W. Kazmierski, Nagaraju Miriyala, Martha De la Rosa et al.· ACS Medicinal Chemistry Lett...· 0 citations
Peroxiredoxin 3 (PRDX3), located in mitochondria, plays a crucial catalytic role in maintaining mitochondrial redox homeostasis and represents a promising target for antitumor drug development. Celastrol is a natural inhibitor of PRDX3; however, it suffers from poor subtype selectivity and high toxicity. In this study, celastrol was used as a lead compound for structural optimization. First, we demonstrated that introducing a triphenylphosphine (TPP) group enables mitochondrial targeting and reduces cytotoxicity. Subsequently, the TPP moiety was exploited as a privileged fragment for further optimization. After two rounds of structural modification, compound 10d was obtained, exhibiting the best antiproliferative activity. Its key structural features include a TPP group attached at the C-3 position and an ethylamine fragment linked at the C-20 position. Compound 10d showed an IC50 value of 0.64 μM against H1975 cells, approximately 3-fold more potent than celastrol. Mechanistic studies revealed that 10d binds to PRDX3 with high affinity (Kd = 0.514 μM), about 17-fold higher than that of celastrol (Kd = 8.56 μM). Furthermore, 10d downregulated the downstream NF-κB and VEGF signaling pathways of PRDX3, effectively suppressing migration and invasion of H1975 cells. In vivo efficacy evaluation demonstrated that 10d exhibited significantly superior tumor suppression in a subcutaneous xenograft model of H1975 tumors compared to celastrol, without causing notable systemic toxicity such as significant body weight loss. In summary, this study successfully developed a highly effective and safe mitochondrially targeted PRDX3 inhibitor, providing a valuable lead compound for the development of innovative drugs targeting tumor redox metabolism.
Yu-Chi Zhao, Hanshuang Cai, Lijuan Zuo et al.· European journal of medicina...· 0 citations
Therapeutic targeting of human Carbonic Anhydrase IX (hCA IX) is critical for cancer treatment, as the enzyme regulates pH homeostasis and facilitates the survival of hypoxic tumor cells. This in silico study presents a multi‐layered computational investigation of a series of 4‐halogenated phenylsulfamates (4: Cl, 5: Br, 6: I) to evaluate their potential as next‐generation inhibitors. Integrated ADME and toxicological profiling predicted strong drug‐like properties, including high gastrointestinal absorption and a favorable safety profile. Specifically, the series exhibits an optimized lipophilic–hydrophilic balance required for effective systemic distribution. Molecular docking and MM‐GBSA binding free energy calculations revealed a clear structure–activity relationship, where para‐halogen substitution maximizes occupancy of the hydrophobic catalytic pocket. Molecular dynamics (100 ns) simulations were employed to evaluate binding stability relative to the clinical standard acetazolamide (AAZ). The lead candidate, 4‐chlorophenyl sulfamate (4), demonstrated enhanced dynamic persistence, maintaining robust Zn‐coordination and a stable hydrogen bond with the gatekeeper residue Thr199 for 99% of the trajectory. It remained in a rigid binding pose (Lig fit on Prot RMSD ∼1.25 Å), suggesting high structural integrity compared to the clinical benchmark. The optimized phenylsulfamate scaffold confers significant stability, identifying these halogenated derivatives as promising leads for future experimental validation.
A. Amin, Omed Qadir Ibrahim, A. K. Ali et al.· ChemistrySelect· 1 citation
Leucine-rich pentatricopeptide repeat containing (LRPPRC), a critical regulator of mitochondrial gene expression, is overexpressed in various malignancies and sustains oxidative phosphorylation (OXPHOS)-dependent adenosine triphosphate (ATP) production essential for tumor growth, chemoresistance, and stem cell survival, rendering it a promising therapeutic target. Herein, using an aptamer-assisted fluorescence polarization platform, we identified acylhydrazone-skeleton inhibitors targeting LRPPRC's RNA-binding domain, leading to the design and synthesis of over 60 derivatives. Lead compound 3o exhibited excellent LRPPRC inhibitory activity (92% at 6.25 μM vs 38% for gossypol acetate (GAA)) and induced robust LRPPRC degradation. Notably, 3o downregulated downstream OXPHOS subunits and ATP synthase, eliciting broad antiproliferative effects, particularly in refractory and drug-resistant A549, BXPC-3, and NCI-H1975 cells (IC50 = 0.54, 0.27, and 1.39 μM, respectively). In PC9 and HCT116 xenografts, 3o achieved tumor growth inhibition (TGI) rates of 73 and 49% with favorable safety profiles. Overall, we developed novel biphenyl-acylhydrazone LRPPRC inhibitors as potent antitumor agents acting via OXPHOS modulation, providing a valuable lead compound for cancer therapy.
Hairu Ren, Jie Liu, Dachi Wang et al.· Journal of Medicinal Chemist...· 0 citations
Dysregulated inflammation is central to chronic diseases such as rheumatoid arthritis and atherosclerosis. In this study, an in-house screening assay identified L464-0189 as a promising anti-inflammatory hit. Based on the phenylthiophene sulfonamide scaffold, 31 novel compounds bearing diverse electronic properties and ring systems were synthesized through multistep reactions. Preliminary structure–activity relationship (SAR) analysis revealed that compounds PTS-15 and PTS-22 significantly inhibited LPS-induced NO production in a concentration-dependent manner. Subsequent biological evaluation demonstrated that PTS-15 and PTS-22 inhibited the gene transcription of IL-1β, IL-6, and TNF-α. In addition, compound PTS-22 significantly inhibited the release of key pro-inflammatory cytokines, including IL-6 and TNF-α. Immunoblotting results further elucidated that PTS-22 exerts its anti-inflammatory efficacy by downregulating the NF-κB signaling pathway, as evidenced by the significant inhibition of p65 phosphorylation. Moreover, molecular docking analysis revealed the potential binding modes of PTS-15 and PTS-22 towards NF-κB. Collectively, these results highlighted the anti-inflammatory potential of phenylthiophene sulfonamide derivatives and supported their further optimization as scaffolds for the development of novel anti-inflammatory therapeutics.
Zhen Dai, Xiuli Yang, Yong Li et al.· RSC Advances· 0 citations
