Structure-activity Relationship Studies Research Articles

Advances on anticancer fungal metabolites: sources, chemical and biological activities in the last decade (2012–2023)

Among microorganisms, fungi are the ones that have the most imagination in producing secondary metabolites with the most varied structural differences, which are produced through different biosynthetic pathways. Therefore, they synthesize secondary metabolites classifiable into numerous families of natural compounds such as amino acids, alkaloids, anthraquinones, aromatic compounds, cyclohexene epoxides, furanones, macrolides, naphthoquinones, polyketides, pyrones, terpenes, etc. They also produced metabolites with very complex structures that can not be classified in the known families of natural compounds. Many fungal metabolites show different biological activities with potential applications in agriculture, food chemistry, cosmetics, pharmacology and medicine. This review is focused on the fungal secondary metabolites with anticancer activity isolated in the last ten years. For some metabolites, when described, their biosynthetic origin, the mode of action and the results of structure activity relationships studies are also reported.Graphical

Bicyclic Pyrrolidine Inhibitors of Toxoplasma gondii Phenylalanine t-RNA Synthetase with Antiparasitic Potency In Vitro and Brain Exposure.

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular, to achieve optimal exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency and ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analogue series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.

Structure-Activity Relationships toward the Identification of a High-Potency Selective Human Toll-like Receptor-7 Agonist.

Toll-like receptor (TLR)-7 agonists are immunostimulatory vaccine adjuvants. A systematic structure-activity relationship (SAR) study of TLR7-active 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine led to the identification of a potent hTLR7-specific p-hydroxymethyl IMDQ 23 with an EC50 value of 0.22 μM. The SAR investigation also resulted in the identification of TLR7 selective carboxamide 12 with EC50 values of 0.32 μM for hTLR7 and 18.25 μM for hTLR8. In the vaccination study, TLR7-specific compound 23 alone or combined with alum (aluminum hydroxide wet gel) showed adjuvant activity for a spike protein immunogen in mice, with enhanced anti-spike antibody production. Interestingly, the adjuvant system comprising carboxamide 12 and alum showed prominent adjuvant activity with high levels of IgG1, IgG2b, and IgG2c in immunized mice, confirming a balanced Th1/Th2 response. In the absence of any apparent toxicity, the TLR7 selective agonists in combination with alum may make a suitable vaccine adjuvant.

Targeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes

Microbial Ni2+ homeostasis underpins the virulence of several clinical pathogens. Ni2+ is an essential cofactor in urease and [NiFe]-hydrogenases involved in colonization and persistence. Many microbes produce metallophores to sequester metals necessary for their metabolism and starve competing neighboring organisms. The fungal metallophore aspergillomarasmine A (AMA) shows narrow specificity for Zn2+, Ni2+, and Co2+. Here, we show that this specificity allows AMA to block the uptake of Ni2+ and attenuate bacterial Ni-dependent enzymes, offering a potential strategy for reducing virulence. Bacterial exposure to AMA perturbs H2 metabolism, ureolysis, struvite crystallization, and biofilm formation and shows efficacy in a Galleria mellonella animal infection model. The inhibition of Ni-dependent enzymes was aided by Zn2+, which complexes with AMA and competes with the native nickelophore for the uptake of Ni2+. Biochemical analyses demonstrated high-affinity binding of AMA-metal complexes to NikA, the periplasmic substrate-binding protein of the Ni2+ uptake system. Structural examination of NikA in complex with Ni-AMA revealed that the coordination geometry of Ni-AMA mimics the native ligand, Ni-(l-His)2, providing a structural basis for binding AMA-metal complexes. Structure-activity relationship studies of AMA identified regions of the molecule that improve NikA affinity and offer potential routes for further developing this compound as an anti-virulence agent.

Ultrasound-assisted synthesis of novel Schiff bases from 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde and their cytotoxicity, apoptosis, cell cycle, molecular docking, and ADMET profiling

With the ultimate goal of discovering new anticancer agents, this study involved the design and synthesis of fifteen novel Schiff bases 4a,b, 5, 6a–d, 7a–e, and 8–10 which contain 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole moiety. The synthetic method depended on reaction of 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (3) with a series of aromatic and heteroaryl amines under ultrasound irradiation to explore the influence of aromatic and heteroaryl rings on biological activity. The chemical structures of these Schiff bases were fully elucidated using various spectral and elemental analyses. The antiproliferative activities of the Schiff bases were studied by the standard SRB method. Among the new 15 Schiff bases, derivatives 4a,b, 5, and 7b have significant cytotoxic effects against PC3, HepG2, and HCT116 cancer cell lines. These four bioactive Schiff bases significantly increased the late apoptosis of all studied tumor cells. Also, both products 4a and 4b arrested the cell cycle at the G1 phase, while both compounds 5 and 7b arrested the S and G2 phases against PC3 cells. In addition, the products 4a, 4b, 5, and 7b have promising high abilities to arrest the cell cycle at the G2 phase against HepG2 and HCT116 cells. The different substitutions on the aryl ring were the basis for the structure–activity relationship study. The molecular docking study confirmed good binding interactions of these compounds with Cyclin-dependent kinase 8 (CDK-8) receptor, while the absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction supported that these bioactive products can be promising anticancer agents.

Computer-Aided Design of Novel Active Components in Plant Protection

The production demands highly specific environmentally and toxicologically acceptable plant protection products are increasing. Computer-aided molecular design of new active components has a great deal in developing plant protection products to avoid that long-lasting and expensive process. Computational design of future compounds and their synthesis, evaluation of their effectiveness on harmful and beneficial organisms in the soil, as well as detailed research mechanism of action at the molecular level, represents an initial stage in the long-lasting and expensive process of plant protection products. In this paper, the recent advances in quantitative structure-activity relationship (QSAR) studies, molecular docking, and calculation of “Pesticidelikeness properties “, as well, have been reviewed. QSAR models for antifungal activities against phytopathological fungi were obtained for the thiazoline and coumarine derivatives, coumarinyl Schiff bases, and coumarin-1,2,4-triazoles. A molecular docking study revealed that antifungal activities of fluorinated pyrazole aldehydes are related to the inhibition of proteinase K, coumarinyl Schiff bases with endoglucanase and pectinase, hybrids of coumarins and 1,2,4-triazoles with sterol 14α-demethylase inhibition, 3-gydroxycoumarin chitin synthase, while γ-thionins strongly binds to fungal membrane moieties.

Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [177Lu]Lu-PSMA-617 in Healthy Organs.

Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [177Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure-activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [177Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.

Design, Synthesis, and Biological Activity of Novel Triketone-Containing Phenoxy Nicotinyl Inhibitors of HPPD.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 μM, demonstrating superior activity compared with mesotrione (0.28 μM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.

Molecular Mechanistic Insights into Dipeptidyl Peptidase-IV Inhibitory Peptides to Decipher the Structural Basis of Activity.

Dipeptidyl peptidase-IV (DPP-IV) inhibiting peptides have attracted increased attention because of their possible beneficial effects on glycemic homeostasis. However, the structural basis underpinning their activities has not been well understood. This study combined computational and in vitro investigations to explore the structural basis of DPP-IV inhibitory peptides. We first superimposed the Xaa-Pro-type peptide-like structures from several crystal structures of DPP-IV ligand-protein complexes to analyze the recognition interactions of DPP-IV to peptides. Thereafter, a small set of Xaa-Pro-type peptides was designed to explore the effect of key interactions on inhibitory activity. The intramolecular interaction of Xaa-Pro-type peptides at the first and third positions from the N-terminus was pivotal to their inhibitory activities. Residue interactions between DPP-IV and residues of the peptides at the fourth and fifth positions of the N-terminus contributed significantly to the inhibitory effect of Xaa-Pro-type tetrapeptides and pentapeptides. Based on the interaction descriptors, quantitative structure-activity relationship (QSAR) studies with the DPP-IV inhibitory peptides resulted in valid models with high R2 values (0.90 for tripeptides; 0.91 for tetrapeptides and pentapeptides) and Q2 values (0.33 for tripeptides; 0.68 for tetrapeptides and pentapeptides). Taken together, the structural information on DPP-IV and peptides in this study facilitated the development of novel DPP-IV inhibitory peptides.

Study on β-glucosidase activators by 3D-QSAR, molecular docking and molecular dynamics simulation

To investigate the conformational relationship and mechanism of action of β-glucosidase (BGL) activators, a theoretical study of three-dimensional quantitative structure activity relationship, molecular docking, molecular dynamics (MD) simulations, and binding free energy analysis were performed. The results indicate that comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models had good stability and predictive ability, with r2cv/ r2pred values of 0.540/0.998 and 0.654/0.993, respectively. The derived contour maps of steric, electrostatic, and hydrogen bond donor field further displayed the modified information of these activators. Molecular docking and MD were performed on calcium diascorbate (CaAS) and L-Ascorbyl 2,6-Dipalmitate (L-ADP), which have good activating ability. The study indicates a positive interaction between the activators and the enzyme, and this interaction does not cause irreversible negative effects on the conformation of BGL. The MD results show that the total binding free energies of CaAS and L-ADP with BGL were −19.837 kJ/mol and −37.798 kJ/mol, respectively, and the binding force of the activators with BGL was mainly derived from hydrophobic interaction and hydrogen bonding. This study offers important guidance for the efficient use of BGL and for the research and development of effective activators.

A deconstruction-reconstruction strategy for pyrimidine diversification.

Structure-Activity Relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates.1-3 Here, we present an alternative approach where we convert pyrimidine-containing compounds various other nitrogen heteroaromatics. Transforming pyrmidines into their correspondingN-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles.4 In effect, this approach allows heterocycle formation on complex molecules, resulting in analogs that would be challenging to obtain by other methods. We anticipate this deconstruction-reconstruction strategy will extend to other heterocycle classes.

Verbascoside and rare flavone glucosides from Citharexylum spinosum L. flowers as antihyperglycemic agents: Isolation, α-amylase inhibition, molecular docking and drug-likeness prediction

Human concern for its public health has been a cornerstone since ancient times, with humans exploring natural resources in their environment for medicinal purposes. Plants have long served as the primary source of medicinal compounds, reflecting centuries of exploration and experimentation. Today, leveraging cognitive and technological advancements, researchers continue to deepen their studies towards achieving optimal health conditions. In pursuit of antihyperglycemic phyto-alternatives, a phytochemical investigation of EtOAc and n-BuOH flower extracts of Citharexylum spinosum L. yielded four rare flavone glucosides viz. cirsilineol 4′-glucoside, jaceoside, 5,4′-dihydroxy-7,3′-dimethoxyflavone 6-glucoside and pedaliin. Additionally, the flavone aglycone apigenin, and the phenylethanoid glycoside verbascoside were isolated. The flavonoid compounds were isolated for the first time from C. spinosum tree. The extracts underwent silica gel column chromatography for simplification, followed by compound purification using preparative HPLC. Molecular structures were elucidated through NMR spectroscopic experiments, spectrometric ESI-HRMS analysis, and comparisons with existing literature data. Subsequently, extracts and isolated compounds were evaluated for their antihyperglycemic activities by assessing their ability to inhibit α-amylase enzymatic activity. EtOAc and n-BuOH extracts displayed important anti-α-amylase properties with IC50 values of 52.5 ± 1.2 and 36.3 ± 1.1 µg/mL, respectively. The results demonstrated promising inhibitory properties of the α-amylase enzyme by the polyphenols isolated in this study. IC50 values ranged from 12.8 ± 0.1 to 23.2 ± 0.1 µM for the isolated compounds, comparable to the reference standard acarbose (IC50= 12.3 ± 0.1 µM). Furthermore, a structure-activity relationship study was conducted, with all isolated molecules docked to the α-amylase enzyme (PDB: 7TAA) and their drug-likeness properties predicted.

Synthesis, antifungal evaluation, 2D-Quantitative structure activity relationship and molecular docking studies of isoxazole derivatives as potential fungicides.

Sheath blight and bakanae disease, prominent among emerging rice ailments, exert a profound impact on rice productivity, causing severe impediments to crop yield. Excessive use of older fungicides may lead to the development of resistance in the pathogen. Indeed, a pressing and immediate need exists for novel, low-toxicity and highly selective fungicides that can effectively combat resistant fungal strains RESULTS: A series of 20 isoxazole derivatives were synthesized using alkoxy/halo acetophenones and N,N-dimethylformamidedimethylacetal. These compounds were characterized by various spectroscopic techniques viz. 1H NMR, 13C NMR and LC-HRMS and were evaluated for their fungicidal activity against Rhizoctonia solani and Fusarium fujikuroi. Compound 5n (5-(2-chlorophenyl) isoxazole) exhibited highest activity (ED50 = 4.43 μg mL-1) against R. solani, while 5p (5-(2,4-dichloro-2-hydroxylphenyl) isoxazole) exhibited highest activity (ED50 = 6.7 μg mL-1) against F. fujikuroi. 2D-Quantitative Structural Activity Relationship (2D-QSAR) analysis, particularly MLR (Model 1), highlighted chi6chain and DistTopo as the key descriptors influencing fungicidal activity. Molecular docking studies revealed the potential of these isoxazole derivatives as novel fungicides targeting sterol 14α-demethylase enzyme, suggesting their importance as crucial intermediates for the development of novel and effective fungicides. All test compounds were effective in inhibiting both fungi, according to the QSAR model, various descriptors such as structural, molecular shape analysis, electronic, and thermodynamic play an important role. Molecular docking studies confirmed that these compounds can potentially replace commercially available fungicides and help control fungal pathogens in rice crops effectively. This article is protected by copyright. All rights reserved.

Design of acyl salicylic acid derivates as COX-1 inhibitors using QSAR approach, molecular docking and QSPR analysis

Background: Acetylsalicylic acid (aspirin), widely used as an antiplatelet agent, is more likely to inhibit COX-1. Along with discovering the cardioprotective role of COX-1 in controlling platelet aggregation, it is important to develop a selective COX-1 inhibitor. Objective: This study aims to design acyl salicylic acid derivatives intended as COX-1 inhibitors. Method: Fourteen derivatives (AcS1-14) were subjected to a quantitative structure-activity relationship (QSAR) study, and 31 QSAR models were obtained using multiple linear regression (MLR) analysis. Molecular docking was performed on COX-1 (PDB. 1PTH) using the Molecular Orbital Environment (MOE) program ver2022.02, and QSPR analysis was conducted to ascertain the contribution of physicochemical descriptors to the free energy score (S) of ligand-receptor complexes. Results: The QSAR-Hansch model predicted hydrophobicity (LogP) and molecular energy (Etotal) and contributed to pain inhibitory action. All derivatives displayed higher in silico affinity than aspirin (S= -4.33±0.00 kcal/mol), and compound AcS7 afforded the highest (S= -5.32 kcal/mol). In QSPR, Etotal also revealed a positive contribution to the affinity. AcS1, AcS2, AcS5, AcS7, and AcS8 expressed higher drug-like properties than aspirin. Conclusion: Derivatives with optimum hydrophobicity and high energy would generate potent COX-1 inhibition. The five selected compounds were recommended to be developed as drug candidates for COX-1 inhibitors.

Cytotoxicity of acridinium-based ionic liquids: structure-activity relationship and mechanistic studies

Ionic liquids (ILs) are a class of low melting point salts with physicochemical properties suitable for a range of industrial applications such as chemical processing and battery design. Major challenges to the wide-scale adoption of ILs in industry include their eco- and cytotoxic effects, however, this opens up the possibility of the use of ILs use as novel anticancer agents. Understanding the structural features that promote IL cytotoxicity is therefore important. Key structural features that can impact IL cytotoxicity include size and lipophilicity of the cationic head group. In this study, the cytotoxic effects of acridinium-based ILs containing relatively large tri- and tetracyclic cations were evaluated. It was found that 9-phenylacridinium-based ILs are potent cytotoxic agents that reduce the viability of human MDA-MB-231 breast cancer cells with IC50 concentrations in the nanomolar range. In mechanistic studies, it was found that unlike the pyridinium-based analogue, [C16Py][I], acridinium-based ILs did not inhibit oxidative phosphorylation or induce reactive oxygen species formation, and may instead target other mitochondrial processes or components such as mitochondrial DNA.

Bridging the maytansine and vinca sites: cryptophycins target β-tubulin’s T5-loop

Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known to date; however, their exact molecular mechanism of action remains unclear. Here, we present the 2.2 Å resolution X-ray crystal structure of a potent cryptophycin derivative bound to the αβ-tubulin heterodimer. The structure addresses conformational issues present in a previous 3.3 Å resolution cryo-electron microscopy structure of cryptophycin-52 bound to the maytansine site of β-tubulin. It further provides atomic details on interactions of cryptophycins, which had not been described previously, including ones that are in line with structure-activity relationship (SAR) studies. Interestingly, we discovered a second cryptophycin-binding site that involves the T5-loop of β-tubulin, a critical secondary structure element involved in the exchange of the guanosine nucleotide and in the formation of longitudinal tubulin contacts in microtubules. Cryptophycins are the first natural ligands found to bind to this new "βT5-loop site” that bridges the maytansine and vinca sites. Our results offer unique avenues to rationally design novel MTAs with the capacity to modulate T5-loop dynamics and to simultaneously engage multiple β-tubulin binding sites.

Mixed N‐heterocyclic carbene and benzyl‐, phenethyl‐, and biphenylamine coordinated Pd complexes: Anticancer activities and stereo‐electronic effects

A series of mixed N‐heterocylic carbene (NHC) palladium complexes bearing C^N bidentate ligands derived from benzylamine, phenethylamine, and biphenylamine were prepared and fully characterized by NMR spectroscopy, ESI‐MS spectrometry, and X‐ray diffraction analyses. The complexes were potent in inhibiting proliferation of HepG2 and Caco2 cancer cells, and a SAR (structure–activity relationship) study revealed C^N ligands with stronger electron donation and moderate steric hindrance are more cytotoxic. DNA binding study through UV–vis absorption titration indicated that such complexes bound stronger to CT‐DNA molecules with higher binding constants. Additional molecular docking of the best performer suggested a groove binding mode through hydrogen bonding and π‐π stacking interactions. The apoptosis induced by the two best performers of α,α‐dimethylbenzylamine and S‐α‐methylbenzylamine ligated complexes was further analyzed by morphology change, cell cycle distribution, ROS production, and mitochondrial membrane potential studies.

[Syntheses and Structure-Activity Relationship Studies of Antitumor Bicyclic Hexapeptide RA-VII Analogues].

A series of antitumor bicyclic hexapeptide RA-VII analogues modified at residue 2, 3, or 6 were prepared by the chemical transformation of the hydroxy, methoxy, or carboxy groups or the aromatic rings of natural peptides RA-II, III, V, VII, and X. Analogues with modified side chains or peptide backbones, which cannot be prepared by the chemical transformation of their natural peptides, and newly isolated peptides from Rubia cordifolia roots were synthesized by using protected cycloisodityrosines prepared by the degradation of bis(thioamide) obtained from RA-VII or the diphenyl ether formation of boronodipeptide under the modified Chan-Lam coupling reaction conditions. Studies of the conformational features of the analogues and the newly isolated peptides and their relationships with cytotoxic activities against the HCT-116, HL-60, KATO-III, KB, L1210, MCF-7, and P-388 cell lines revealed the following: the methoxy group at residue 3 is essential for the potent cytotoxic activity; the methyl group at Ala-2 and Ala-4 but not at D-Ala-1 is required to establish the bioactive conformation; the N-methyl group at Tyr-5 is necessary for the peptides to adopt the active conformation preferentially; and the orientation of Tyr-5 and/or Tyr-6 phenyl rings has a significant effect on the cytotoxic activity.

Synthesis, Structure-activity Relationship, and Biological Activity of Benzimidazole-quinoline: A Review to Aid in the Design of a New Drug

Abstract: Heterocyclic compounds are fundamental building blocks for developing novel bioactive compounds. Due to their extensive uses in both industrial and synthetic organic chemistry, quinoline and benzimidazole have recently become important heterocycles. Clinical trials have investigated quinoline and benzimidazole analogues to treat a variety of illnesses, including cancer, bacterial and fungal infection, DNA damage, etc. Medicinal chemists are paying attention to nitrogen-containing hybrid heterocyclic compounds that have a wide range of therapeutical potential with lesser adverse effects. Many efforts have been made to find new and more efficient ways to synthesize these molecules. However, microbial resistance is becoming a major threat to the scientific community; hence, the necessity for the discovery and development of novel antimicrobial drugs with novel modes of action is becoming highly significant. One strategy to overcome this problem is to produce hybrid molecules by combining two or more bioactive heterocyclic moieties in a single molecular platform. Based on established research data on quinoline- bearing benzimidazole derivatives, it can be concluded that both moieties are used for the synthesis of promising therapeutically active agents. This present review comprises the synthetic approaches of biologically active quinolines containing benzimidazole derivatives with their structure-activity relationship studies to provide an overview of the work done on quinoline derivatives to the medicinal chemist for future research.

Identification of Selective Imidazopyridine CSF1R Inhibitors.

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.