Structure-activity Relationship Studies Research Articles

Cheminformatics-driven prediction of BACE-1 inhibitors: Affinity and molecular mechanism exploration

The β-secretase, sometimes referred to as BACE1 or Asp2, is the enzyme responsible for initiating the production of Aβ by breaking down the amyloid precursor protein. Hence, BACE is a pivotal target for pharmacological intervention aimed at diminishing the production of Aβ in Alzheimer's disease (AD). We did a quantitative structure-activity relationship (QSAR) study on 1235 compounds that had been experimentally reported as BACE-1 inhibitors (Ki) to find the target molecule and structural patterns linked to blocking the BACE-1 receptor. The OECD-recommended genetic algorithm-multiple linear regression (GA-MLR) QSAR model strikes a good balance between being able to make accurate predictions and understanding how things work. It achieves high values for many evaluation metrics, including R2tr = 0.8047, Q2LMO = 0.802, R2ex = 0.805, CCCex = 0.891, Q2-F1=0.801, Q2-F2=0.799, and Q2-F3=0.815. The mechanistic interpretation of QSAR has identified some nitrogen atoms that are required to block beta-secretase and make it less effective at doing its job. A positively charged aromatic carbon atom has a more significant impact on beta-secretase-1 inhibition. The docking study showed that the catalytic dye residues Asp32 and Asp228 become protonated when compound 27 is present, but they stay unprotonated when compound 27 is not present. These rings of pyrazine and pyridine interact hydrophobically with Tyr71 and Ile118 residues, confirming the pharmacophoric features seen in the QSAR data. We examined the stability of both the protein-ligand complex and the apo-protein. The apoprotein had an average gyration radius of 22.13, whereas the protein-ligand complex had an average gyration radius of 22.91. No changes were made to the results from the molecular docking, molecular dynamics (MD) simulation, MMGBSA (Molecular Mechanics Generalized Born Surface Area), or DFT analyses. Therefore, the current work could effectively contribute to the future development of BACE inhibitors in medication design.

Structural insights into alterations in the substrate spectrum of serine-β-lactamase OXA-10 from Pseudomonas aeruginosa by single amino acid substitutions

ABSTRACT The extensive use of β-lactam antibiotics has led to significant resistance, primarily due to hydrolysis by β-lactamases. OXA class D β-lactamases can hydrolyze a wide range of β-lactam antibiotics, rendering many treatments ineffective. We investigated the effects of single amino acid substitutions in OXA-10 on its substrate spectrum. Broad-spectrum variants with point mutations were searched and biochemically verified. Three key residues, G157D, A124T, and N73S, were confirmed in the variants, and their crystal structures were determined. Based on an enzyme kinetics study, the hydrolytic activity against broad-spectrum cephalosporins, particularly ceftazidime, was significantly enhanced by the G157D mutation in loop 2. The A124T or N73S mutation close to loop 2 also resulted in higher ceftazidime activity. All structures of variants with point mutations in loop 2 or nearby exhibited increased loop 2 flexibility, which facilitated the binding of ceftazidime. These results highlight the effect of a single amino acid substitution in OXA-10 on broad-spectrum drug resistance. Structure–activity relationship studies will help us understand the drug resistance spectrum of β-lactamases, enhance the effectiveness of existing β-lactam antibiotics, and develop new drugs.

Base-Promoted Ring Expansion Reaction of 4-Quinolones To Access Benzazepinones.

4-Quinolone derivatives undergo an unexpected ring expansion reaction with α-halo esters/phosphonates/sulfones in the presence of a base, such as NaH, to produce novel benzazepinones. Under these mild and transition-metal-free conditions, most substrates gave moderate to excellent yields. The reaction could be applied in gram-scale synthesis of drug-like molecules that greatly accelerated our structure-activity relationship studies. A plausible mechanism was proposed.

Facile One-Pot Conversion of (poly)phenols to Diverse (hetero)aryl Compounds by Suzuki Coupling Reaction: A Modified Approach for the Synthesis of Coumarin- and Equol-Based Compounds as Potential Antioxidants.

A series of 16 (hetero)aryl compounds based on coumarin and equol has been efficiently synthesized by exploring the palladium-catalyzed Suzuki cross-coupling reactions. Polyphenol based on coumarin (4-methyl-7-hydroxy coumarin) was initially converted to corresponding coumarin imidazylate and then subjected to Suzuki coupling reaction with 4-methoxyphenylboronic acid to obtain the coupled product. This modified approach was later developed into a one-pot methodology by directly reacting the polyphenol with 1,1-sulfonyldiimidazole (SDI) and boronic acid in situ to obtain the Suzuki coupled product in one step. Moreover, an array of (poly)phenols based on coumarin and equol were later converted to diverse (hetero)aryl compounds by this optimized step-economic protocol. The synthesized compounds were then subjected to the screening of their potential antioxidant activities by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. In our investigation, the compounds 4ah, 4eh, 4gh and 4hh exhibited promising antioxidant potential when compared to the reference standard, butylated hydroxytoluene (BHT). Structure activity relationship (SAR) studies revealed the importance of the presence of electron-donating substituents in enhancing the antioxidant activity of the synthesized compounds.

Widely-targeted in silico and in vitro evaluation of veratrum alkaloid analogs as FAK inhibitors and dual targeting of FAK and Hh/SMO pathways for cancer therapy: A critical analysis

Focal Adhesive Kinase (FAK), a key player in aggressive cancers, mediates signals crucial for progression, invasion, and metastasis. Despite advances in targeted therapies, drug resistance is still a challenge, and survival rates remain low, particularly for late-stage patients, emphasizing the need for innovative cancer therapeutics. Cyclopamine, a veratrum alkaloid, has shown promising anti-tumor properties, but the search for more potent analogs with enhanced affinity for the biological target continues.This study employs a hybrid virtual screening approach combining pharmacophore model-based virtual screening (PB-VS) and docking-based virtual screening (DB-VS) to identify potential inhibitors of the FAK catalytic domain. PB-VS on the PubChem database yielded a set of hits, which were then docked with the FAK catalytic domain in two stages (1st and 2nd DB-VS). Hits were ranked based on docking scores and interactions with the active site. The top three compounds underwent molecular dynamics simulations, alongside two control compounds (SMO inhibitor(s) and FAK inhibitor(s)), to assess stability through RMSD, RMSF, Rg, and SASA analyses. ADMET properties were evaluated, and compounds were filtered based on drug-likeness criteria.Molecular dynamics simulations demonstrated the stability of compounds when complexed with the FAK catalytic domain. Compounds 16 (−25 kcal/mol), 88 (−27.47 kcal/mol), and 87 (−18.94 kcal/mol) exhibited comparable docking scores, interaction profiles, stability, and binding energies, indicating their potential as lead candidates. However, further validation and optimization through quantitative structure-activity relationship (QSAR) studies are essential to refine their efficacy and therapeutic potential. The in vitro cell-based assay demonstrated that compound 101PF, a FAK inhibitor, significantly inhibited the proliferation and migration of A549 cells. However, the results regarding the combined effects of FAK and SMO inhibitors were inconclusive, highlighting the need for further investigation. This study contributes to developing more effective anti-cancer drugs by improving the understanding of potential cyclopamine-based veratrum alkaloid analogs with enhanced interactions with the FAK catalytic domain.

Design, synthesis and biological evaluation of thienopyridine derivatives as c-Met kinase inhibitors.

With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3-b] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC50 values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581μM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.

Pinonic Acid Derivatives Containing Thiourea Motif: Promising Antifungal Lead Compound Targeting Cellular Barrier of Colletotrichum fructicola.

In order to explore novel antifungal lead compounds from plant essential oil, thirty-two pinonic acid derivatives containing thiourea groups were designed and synthesized using α-pinene as a raw material. One of these pinonic acid derivatives compound 3a exhibited noteworthy in vitro antifungal activity against Colletotrichum fructicola (EC50 = 9.22 mg/L), which was comparable to that of the positive control kresoxim-methyl (EC50 = 9.69 mg/L). Structure-activity relationship (SAR) studies demonstrated that the introduction of thiourea groups, F atoms, and Cl atoms into the structure of pinonic acid derivatives significantly improved their antifungal activity. The in vivo antifungal test revealed that compound 3a could effectively control pear anthracnose. It also proved that compound 3a showed low acute oral toxicity to honeybees (LD50 > 100 μg/bee) and low or no cytotoxicity to LO2 and HEK293 cell lines. The preliminary mechanism of action studies revealed that compound 3a caused mycelium deformity, increased cell membrane permeability, blocked the normal process of phospholipase C on the cell membrane, and reduced mycelium protein content. The results of molecular docking studies demonstrated the stable binding of compound 3a to phospholipase C and chitin synthetase. This study suggested that compound 3a could be used as a promising lead compound for the development of novel antifungal agents targeting the cellular barrier of C. fructicola.

2'-Fluorinated nucleoside chemistry for new drug discovery: achievements and prospects.

Fluorinated nucleosides are an important class of modified nucleosides that have demonstrated therapeutic potential for treating various human diseases, especially viral infections and cancer. Many fluorinated nucleosides have advanced into clinical trials or have been approved by the FDA for use in patients. Among these fluorinated nucleosides, azvudine, developed by us, has been officially approved by the National Medical Products Administration for the treatment of coronavirus disease 2019 (COVID-19) and human immunodeficiency virus, indicating the therapeutic promise of fluorinated nucleosides. In view of the therapeutic promise of fluorinated nucleosides for antiviral and anticancer therapy, in this Review we will provide a comprehensive overview of well-established 2'-fluorinated nucleosides approved for use in the market or those in clinical stages for antiviral and antitumor therapies, highlighting the drug discovery strategies, structure-activity relationship studies, mechanisms of action, and preclinical/clinical studies and also discuss the challenges and future directions for nucleoside-based new drug discovery.

Exploration of thiazine Schiff bases as promising urease inhibitors: Design, synthesis, enzyme inhibition, kinetic analysis, ADME/T evaluation, and molecular docking studies

Urease catalyzes the hydrolysis of urea, leading to an increase in stomach pH and supporting Helicobacter pylori survival, which is linked to several gastrointestinal disorders. In this study, thiazine-based Schiff bases were explored as promising urease inhibitors. Various spectroscopic techniques characterized the synthetic library of thiazine Schiff bases 2–36 and also evaluated for their inhibitory activities against urease. The derivatives demonstrated significant inhibitory potential with IC50 values ranging from 0.14 ± 0.08 to 3.66 ± 0.21 μM, outperforming the standard inhibitor thiourea (IC50 = 19.43 ± 0.18 μM). Structure-activity relationship (SAR) studies revealed that specific substitutions (type and positions) on the aryl ring significantly affect the inhibition potential. The most potent derivative, compound 7, possessed 2-methoxy-5-trifluoromethyl substitutions and exhibited an IC50 of 0.14 ± 0.08 μM. Enzyme kinetics studies revealed that the most potent derivatives function as competitive inhibitors. Additionally, molecular docking studies provided insights into the binding interactions between the molecule and the urease active site, highlighting key residues involved in inhibitor binding. These findings highlight the therapeutic potential of thiazine-based Schiff bases as urease inhibitors and provide insights for the development of new anti-ulcer agents.

Novel Dichloroacetophenone-Based PDHK1 Inhibitors as Potent Anticancer Agents.

Pyruvate dehydrogenase kinases (PDHKs), important metabolic and abnormally expressed enzymes in cancer cells, are promising targets for cancer therapy, especially for non-small-cell lung cancer (NSCLC). In this study, a new hit, dichloroacetophenone (DAP) analog 9, was postulated to bind to the PDHK1 allosteric pocket, guided by molecular modeling and kinase biochemical experiments. Based on this binding mode, novel DAP analogs were designed and synthesized to confirm the importance of Phe180, Tyr411, and the hydrophobic core at the bottom of the pocket. This structure-activity relationship (SAR) study led to the discovery of a novel potent hybrid scaffold, dichloroacetophenone biphenylsulfone ether. Dichloroacetophenone biphenylsulfone ether 31 and 32 inhibited PDHK1 with IC50 values of 86 and 140 nM, respectively. Compound 32 with acceptable in vitro metabolic stability, predicted drug-likeness properties and ADME/T profiles, showed promising therapeutic efficacy in a lung cancer xenograft mouse model.

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer.

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 μM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

Schiff Bases: A Captivating Scaffold with Potential Anticonvulsant Activity.

One of the most important organic compounds, also known as a Schiff base, imine, or azomethine, has been associated with several biological processes. The group is a component of both natural or synthetic chemicals and functions as both a precursor and an intermediary in the synthesis of therapeutically active substances. The review highlights the various non-metal Schiff bases' structure-activity relationship (SAR) studies, general model, docking, and design approach for anticonvulsant actions. Schiff bases serve as linkers in numerous synthetic compounds with a variety of activities, according to the findings of several investigations. As a result, the current review will give readers a thorough understanding of the key ideas put forth by different researchers regarding the anticonvulsant properties of Schiff bases. It will serve as a valuable information source for those planning to synthesize new anticonvulsant molecules that contain Schiff bases as pharmacophores or biologically active moieties.

Design, synthesis, and biological evaluation of imidazo[4,5-b]pyridine mitochondrial uncouplers for the treatment of metabolic dysfunction-associated steatohepatitis (MASH)

Small molecule mitochondrial uncouplers have gained traction for their potential therapeutic use against metabolic dysfunction-associated steatohepatitis (MASH). Herein, we report a novel imidazo[4,5-b]pyridine scaffold derived from iterative modifications of the potent uncoupler BAM15. Our structure-activity relationship (SAR) study demonstrated that this promising scaffold has a range of tolerated substitutions that allows for the modulation of uncoupling activity and in vivo pharmacokinetic properties. Specifically, compound SHS206 displayed an EC50 of 830 nM in L6 myoblasts and, importantly, showed no cytotoxicity in vitro or adverse effects in mice up to 1000 mg/kg. SHS206 was administered orally at 100 and 300 mg/kg in a GAN mouse model of MASH and was observed to lower liver triglyceride levels while food intake, body weight, temperature, organ weights, and cholesterol levels remained unaltered. Together, these findings illuminate imidazo[4,5-b]pyridine as a promising scaffold for the future development of mitochondrial uncouplers.

Biological evaluation of signal transducer and activator of transcription 3 (STAT3) targeting by phaeosphaeride A and its analogs

The inhibitory activities of phaeosphaeride A (PPA), phaeosphaeride B, and four synthetic derivatives against phosphorylation of signal transducer and activator of transcription 3 (STAT3) and cell proliferation in cervical (HeLa) and breast (MDA-MB-231) cancer cells were evaluated. PPA inhibited IL-6-induced STAT3 phosphorylation and cell proliferation at similar concentrations. The structure–activity relationship studies revealed that the enantiomer of PPA was the most potent of the evaluated phaeosphaerides in both inhibiting STAT3 phosphorylation and cell growth. PPA clearly inhibited the IL-6-activated STAT3 signaling pathway. However, the presence or absence of activation of the STAT3 signaling pathway in cells showed no relationship to the antiproliferative activity. Notably, the possible covalent bond-forming ability of PPA was critical for its biological activities.

2-Aminobenzothiazole based adjuvant of polymyxin E against Gram-negative bacteria

Antibiotic resistance has emerged as a pressing global health issue. Polymyxin E, commonly regarded as a clinically important antibiotic, faces limitations due to its dose-dependent toxicity. A crucial strategy to combat this is the development of an antibiotic adjuvant to enhance efficacy while reducing dosage. Screening from our extensive in-house compound library, KJ1071 emerged as a promising adjuvant candidate for polymyxin E. Subsequent structure–activity relationship studies led to the discovery of compound A35, which demonstrated superior synergistic activity. However, its limited aqueous solubility posed challenges for biological experiments. To address this, we carried out a structural derivatization aimed at enhancing its solubility. The amino acid derivative A59 notably improved aqueous solubility to 3.237 mg/mL, a substantial 3237-fold increase compared to compound A35. Moreover, A59 amplified the efficacy of polymyxin E in eradicating a variety of Gram-negative bacteria, including certain clinical strains that are resistant to polymyxin E. The mechanism studies indicated that A59 might target the bacterial membrane. These findings suggest that the discovery of this innovative scaffold could provide critical insights for new adjuvant therapies.

Divergent asymmetric reactions of α-alkenyl ketones with β,γ-alkynyl-α-imino esters enabled by chiral phosphoric acids

Divergent asymmetric synthesis provides access to a wide range of isomers from the same starting material by modifying the reaction conditions, which plays an important role in the efficient construction of a structurally diverse molecular library for structure-activity relationship studies. In this work, we present the divergent asymmetric addition of α-alkenyl ketones with β,γ-alkynyl-α-imino esters enabled by chiral phosphoric acid catalysis. Despite the challenging presence of multiple reactive sites in both components, we successfully achieved the regioselective synthesis of both α-1,2-addition α-tertiary amines and γ-1,4-addition allenes with good to high regio-, diastereo- and enantioselectivities by modifying the reaction conditions. Moreover, the stereodivergent asymmetric synthesis of the four allene stereoisomers bearing contiguous central and axial chirality was achieved by adjusting the E/Z configuration of the α-alkenyl ketone substrates.

Total syntheses of mavintramycin A and its structural analog, cytosaminomycin C, and evaluation of their antibacterial activities against Mycobacterium avium and Mycobacterium intracellulare

Mavintramycin A is a new aminohexopyranose nucleoside antibiotic with potent anti-Mycobacterium avium complex (MAC) activity against M. avium and M. intracellulare. Herein, we report the total syntheses of mavintramycin A and its structural analog cytosaminomycin C, which is a known anticoccidial antibiotic. Furthermore, the anti-MAC activities of mavintramycin A, cytosaminomycin C, and their corresponding p-methoxybenzyl-protected analogs were evaluated. Notably, the developed synthetic route enables ready access to various analogs of mavintramycin A for structure-activity relationship studies.

Extended structure-activity relationship studies of the [1,2,5]oxadiazolo[3,4-b]pyrazine-containing colistin adjuvants

Antimicrobial resistance (AMR) is a formidable global health challenge. Multidrug-resistant (MDR) Gram-negative bacterial infections are of primary concern due to diminishing treatment options and high morbidity and mortality. Colistin, a polymyxin family antibiotic, is a last-resort treatment for MDR Gram-negative infections, but its wider use has resulted in escalating resistance. In 2022, using a screening approach, we discovered that a [1,2,5]oxadiazolo[3,4-b]pyrazine (ODP)-containing compound selectively re-sensitized various MDR Gram-negative bacteria to colistin. Initial structure–activity relationship (SAR) studies confirmed that bisanilino ODP compounds are colistin adjuvants with low mammalian toxicity. Herein, we report our extended SAR studies on a wide range of ODP analogs bearing alkyl- or arylalkylamines. Specifically, we discovered two new compounds, 5q and 8g, with potent colistin-potentiating activity and low mammalian toxicity in a wide range of clinically relevant pathogens.

An Overview of Synthetic Derivatives of Thiazole and their Role in Therapeutics

Thiazole derivatives have attracted much attention in medicinal chemistry due to their diverse pharmacological activities. This study provides an overview of the latest synthetic derivatives of thiazole and their therapeutic applications. Innovative methodologies have been adopted to enhance the structural diversity and optimize the pharmacological properties of thiazole-based compounds. These synthetic derivatives exhibit a broad spectrum of therapeutic activities, and understanding the essential features responsible for the observed pharmacological effects has been pivotal in structure-activity relationship studies. Drug development efforts have focused on modulating thiazole derivatives for improved bioavailability, selectivity, and reduced toxicity. This abstract highlight the potential of thiazole derivatives in targeting specific biological activity, paving the way for developing innovative therapeutic agents. Thiazole moiety as a heterocyclic compound was studied for its different pharmacological actions. The derivatives obtained from thiazole possesses diverse therapeutic actions including antimicrobial activity, anti-tubercular activity, anti-diabetic activity, anti-convulsant, anti-inflammatory actions, anti-tumor activities. The mechanism of actions of all these activities also studied by the researcher for providing the scientific evidence and validations of their actions. Utilization of synthetic chemistry for exploration of various pharmacological potential of thiazole derivatives will lead the future pharmacologists for a newer dimension for new drug discovery and also these derivatives can be further optimized for the development of alternative option for the treatment of various diseases. The versatility of thiazole scaffolds presents promising opportunities for discovering new drugs with enhanced efficacy and improved pharmacokinetic profiles. As researchers continue to delve into the synthesis and pharmacological evaluation of thiazole derivatives, their significance in modern drug design and therapy becomes increasingly evident.