Structure-activity Relationship Studies Research Articles

Microwave-assisted synthesis of highly sulfated mannuronate glycans as potential inhibitors against SARS-CoV-2.

Algae-based marine carbohydrate drugs are typically decorated with negative ion groups such as carboxylate and sulfate groups. However, the precise synthesis of highly sulfated alginates is challenging, thus impeding their structure-activity relationship studies. Herein we achieve a microwave-assisted synthesis of a range of highly sulfated mannuronate glycans with up to 17 sulfation sites by overcoming the incomplete sulfation due to the electrostatic repulsion of crowded polyanionic groups. Although the partially sulfated tetrasaccharide had the highest affinity for the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, the fully sulfated octasaccharide showed the most potent interference with the binding of the RBD to angiotensin-converting enzyme 2 (ACE2) and Vero E6 cells, indicating that the sulfated oligosaccharides might inhibit the RBD binding to ACE2 in a length-dependent manner.

Synthetic ramoplanin analogues are accessible by effective incorporation of arylglycines in solid-phase peptide synthesis.

The threat of antimicrobial resistance to antibiotics requires a continual effort to develop alternative treatments. Arylglycines (or phenylglycines) are one of the signature amino acids found in many natural peptide antibiotics, but their propensity for epimerization in solid-phase peptide synthesis (SPPS) has prevented their use in long peptide sequences. We have now identified an optimized protocol that allows the synthesis of challenging non-ribosomal peptides including precursors of the glycopeptide antibiotics and an analogue of feglymycin (1 analogue, 20%). We have exploited this protocol to synthesize analogues of the peptide antibiotic ramoplanin using native chemical ligation/desulfurization (1 analogue, 6.5%) and head-to-tail macrocyclization in excellent yield (6 analogues, 3-9%), with these compounds extensively characterized by NMR (U-shaped structure) and antimicrobial activity assays (two clinical isolates). This method significantly reduces synthesis time (6-9 days) when compared with total syntheses (2-3 months) and enables drug discovery programs to include arylglycines in structure-activity relationship studies and drug development.

Structure control and evolution of atomically precise gold clusters as heterogeneous precatalysts.

Metal clusters have distinct features from single atom and nanoparticle (>1 nm) catalysts, making them effective catalysts for various heterogeneous reactions. Nevertheless, the ambiguity and complexity of the catalyst structure preclude in-depth mechanistic studies. The evolution of metal species during synthesis and reaction processes represents another challenge. One effective solution is to precisely control the structure of the metal cluster, thus offering a well-defined pre-catalyst. The well-defined chemical formula and configurations make atomically precise metal nanoclusters optimal choices. To fabricate an atomically precise metal nanocluster-based heterogeneous catalyst with enhanced performance, careful structural design of both the nanocluster and support material, an effective assembling technique, and a pre-treatment method for these hybrids need to be developed. In this review, we summarize recent advances in in the development of heterogeneous catalysts using atomically precise gold and alloy gold nanoclusters as precursors. We will begin with a brief introduction to the structural properties of atomically precise nanoclusters and structure determination of cluster/support hybrids. We will then introduce heterogeneous catalysts prepared from medium size (tens to hundreds of metal atoms) and low nuclearity nanoclusters. We will illustrate how ligand modification, support-cluster interaction, hybrid fabrication, and heteroatom (Pt, Pd Ag, Cu, Cd, Fe) introduction affect the structural properties and pretreatment/reaction-induced structural evolution of gold nanocluster pre-catalysts. Lastly, we will highlight the synthetic method of NCs@MOF hybrids and their effectiveness in circumventing the adverse cluster structural evolution. These findings are expected to shed light on the structure-activity relationship studies and future catalyst design strategies using atomically precise metal nanocluster pre-catalysts.

Synthesis of cytochalasan analogues with aryl substituents at position 10.

Cytochalasans are fungal metabolites that are known to inhibit actin polymerization. Despite their remarkable bioactivity, there are few studies on the structure-activity relationship (SAR) of the cytochalasan scaffold. The full potential of structural modifications remains largely unexplored. The substituent at position 10 of the cytochalasan scaffold is derived from an amino acid incorporated into the cytochalasan core, thus limiting the structural variability at this position in natural products. Additionally, modifications at this position have only been achieved through semisynthetic or mutasynthetic approaches using modified amino acids. This paper introduces a modular approach for late-stage modifications at position 10 of the cytochalasan scaffold. Iron-mediated cross-coupling reactions with corresponding Grignard reagents were used to introduce aryl or benzyl groups in position 10, resulting in the synthesis of six new cytochalasan analogues bearing non-natural aromatic residues. This methodology enables further exploration of modifications at this position and SAR studies among cytochalasan analogues.

APRENDIZADO DE MÁQUINA APLICADO A QSAR

MACHINE LEARNING APLLIED TO QSAR. Over the years the study of the quantitative structure-activity relationship (QSAR) has transformed from a simple regression analysis to the implementation of machine learning (ML) with multiple statistics. Today ML-based QSAR models are quite important and play a notable role in drug design and screening, property prediction, biological activity, etc. ML methods applied to QSAR build classification or regression models to describe/predict the complex relationships between the chemical structure of molecules and biological activity. Even with the increase in scientific publications addressing this topic written in Portuguese, there is still a shortage of scientific articles explaining ML techniques applied to QSAR, how to build models, the types of models, algorithms, for the Brazilian scientific community. And to fill this need, we intend to approach the subject in a simple and didactic way for students and researchers who are starting in this very promising and important area. We will describe the fully explained theory of machine learning by applying QSAR, abstracting the complexity, and well-illustrated.

Application of tobramycin benzyl ether as an antibiotic adjuvant capable of sensitizing multidrug-resistant Gram-negative bacteria to rifampicin.

The emergence of aminoglycoside resistance has prompted the development of amphiphilic aminoglycoside derivatives which target bacterial membranes. Tobramycin and nebramine ether derivatives initially designed for this purpose were optimized and screened for their potential application as outer membrane (OM) permeabilizing adjuvants. Structure-activity relationship (SAR) studies revealed that the tobramycin benzyl ether was the most optimal OM permeabilizer, capable of potentiating rifampicin, novobiocin, vancomycin, minocycline, and doxycycline against Gram-negative bacteria. The innovative use of this compound as an adjuvant is highlighted by its ability to sensitize multidrug-resistant (MDR) Gram-negative bacteria to rifampicin and restore the susceptibility of MDR Escherichia coli to minocycline.

Nature-derived Alkaloids as a Promising Bioactive Compound in Drug Discovery to Meet Global Leishmania Needs

Background: Natural products have been important resources for potential drug development. Among the many classes of natural products, alkaloids have the most therapeutic applications. Treatment of leishmaniasis by chemical drugs remains a challenge because of toxic side effects, limited efficacy, and drug resistance. This review focuses to embrace all researches on leishmanicidal alkaloids over a specific range of time, with special consideration the molecular mechanism of action, and structure-related activity. Methods: All publications (in English) from Web of Science, PubMed, Science Direct, Scopus, and Google Scholar from 2000-2021 using a variety of keywords such as natural alkaloids, herbal alkaloids, marine alkaloids along with leishmaniasis were included in the present study. In this summary, the focus is mainly on natural alkaloids of plant, mineral, marine origin, etc., which have empirically demonstrated the antileishmanial effect. Results: Fourteen categories of alkaloids with anti-leishmaniasis activity were extracted from the articles. The highest number of alkaloids belonged to isoquinoline, indole, and quinoline alkaloids (21.78%, 20.67%, and 16.48% respectively). This review indicated that the mentioned alkaloids are able to inhibit the proliferation of parasites, the respiratory chain and protein synthesis, arrest the cell cycle, disrupt the mitochondrial membrane integrity, inhibit leishmanial topoisomerase, induce mitochondrial dysfunction, and changes in the parasite morphology. Discussion: The present study highlighted antileishmanial alkaloids that are active against different species of Leishmania in vitro and some of them are also active in visceral and cutaneous leishmaniasis models. However, more clinical studies are needed to clarify the anti-leishmanial activity of alkaloids against leishmania in detail. Conclusion: Among the reported compounds, two main classes of alkaloids including isoquinoline and indole alkaloids cover a wider range of anti-parasitic compounds, and structure-activity relationships (SAR) studies of these molecular skeletons may be good lead compounds and afford the structural clues to develop novel medicines with more selective therapeutic profiles.

N,O-Bidentated difluoroboron complexes based on pyridine-ester enolates: Facile synthesis, post-complexation modification, optical properties, and applications

An array of pyridine-ester enolate based organoboron complexes has been designed and synthesized via a one-pot cascade of Pd-catalyzed α-arylation and BF2 complexation. The rapid structure-activity relationship (SAR) studies indicated that unsymmetrical N,O-chelated BF2 complexes were highly fluorescent in solid state, and exhibited large Stokes shifts, excellent photostability, along with insensitivity to pH. The α-aryl group could not only modulate the electronic effect but also inhibit the intermolecular π-π stacking to promote the aggregation-induced emission (AIE) effect. DFT calculations and experiments identified that the intramolecular charge transfer properties of these N,O-chelates could be switched by the modification of substituents, resulting tunable fluorescence wavelengths. Furthermore, post-complexation modification was accomplished, including Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination, oxidative cleavage, along with a unique triple substitution reaction involving propargyl Grignard reagents. The exemplificative application of dimethylamine substituted boron complex as a reversible acidic vapor sensor was also demonstrated.

Development of Hsp90 C-terminal inhibitors with noviomimetics that manifest anti-proliferative activities.

Inhibition of the Hsp90 C-terminal domain offers a promising opportunity to treat numerous diseases/indications. Furthermore, the development of Hsp90 C-terminal inhibitors (CTIs) is advantageous over N-terminal inhibitors because it avoids the detriments associated with induction of the heat shock response (HSR). However, the lack of co-crystal structures of small molecules bound to the C-terminus have hindered their development. Therefore, structure-activity relationship (SAR) studies have been pursued to optimize such inhibitors. Noviose sugar surrogates, also known as noviomimetics have been prepared to investigate the size and nature of the C-terminal domain binding pocket. Herein, we report the synthesis and anti-proliferative activity manifested by this new series of Hsp90 C-terminal inhibitors.

Design, synthesis and biological evaluation of novel pyrimidine derivatives as bone anabolic agents promoting osteogenesis via the BMP2/SMAD1 signaling pathway.

Anti-resorptive inhibitors such as bisphosphonates are widely used but they have limited efficacy and serious side effects. Though subcutaneous injection of teriparatide [PTH (1-34)] is an effective anabolic therapy, long-term repeated subcutaneous administration is not recommended. Henceforth, orally bio-available small-molecule-based novel therapeutics are unmet medical needs to improve the treatment. In this study, we designed, synthesized, and carried out a biological evaluation of 31 pyrimidine derivatives as potent bone anabolic agents. A series of in vitro experiments confirmed N-(5-bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-yl)hexanamide (18a) as the most efficacious anabolic agent at 1 pM. It promoted osteogenesis by upregulating the expression of osteogenic genes (RUNX2 and type 1 col) via activation of the BMP2/SMAD1 signaling pathway. In vitro osteogenic potential was further validated using an in vivo fracture defect model where compound 18a promoted the bone formation rate at 5 mg kg-1. We also established the structure-activity relationship and pharmacokinetic studies of 18a.

Discovery, synthesis, activities, structure-activity relationships, and clinical development of combretastatins and analogs as anticancer drugs. A comprehensive review.

Covering: 1982 to up to the end of 2022Bioassay guided purification of the extracts of Combretum caffrum led to the discovery of six series of combretastatins A-D with cytotoxic activities ranging from sub nM to >50 μM ED50's against a wide variety of cancer cell lines. Of these, cis-stilbenes combretastatins A-4 and A-1 were the most potent, exhibiting in vivo efficacy against a wide variety of tumor types in murine models. These antimitotic agents inhibited tubulin polymerization by reversibly binding to the colchicine binding sites. They inhibited tumor growth by a novel antivascular and antineogenesis mechanism in which they stopped blood flows to the blood vessels causing necrosis. Over 20 clinical trials of the phosphate prodrugs of combretastatin A-4 (CA4P) and A-1 (CA1P) showed objective and stable responses against many tumor types, with increased survival times of many patients along with the confirmed cure of certain patients inflicted with anaplastic thyroid cancers. Medicinal chemistry efforts led to the identification of three new leads (AVE8062, BNC105P, SCB01A) with improved in vitro and in vivo potency and an often-improved cellular spectrum. Unfortunately, these preclinical improvements did not translate clinically in any meaningful way. Objectively, CA4P remained the best compound and has garnered many Orphan drug designations by FDA. Clinical trials with tumor genetic mapping, particularly from previous responders, may help boost the success of these compounds in future studies. A comprehensive review of combretastatin series A-D, including bioassay guided discovery, total syntheses, and structure-activity relationship (SAR) studies, biological and mechanistic studies, and preclinical and clinical evaluations of the isolated combretastatins and analogs, along with the personal perspective of the author who originated this project, is presented.

QSAR of SARS-CoV-2 Main Protease Inhibitors Utilizing Theoretical Molecular Descriptors

Background: COVID-19 is caused by a novel strain of severe acute respiratory syndrome coronaviruses (SARS-CoV-2). It has claimed casualties around the world since the end of 2019 due to its high virulence and quick multiplicity in the human body. Hence, there has been a requirement to develop effective remedial measures to mitigate the mortality. Scientists have been able to develop corona vaccines to provide immunity, but there are no specific small-molecule chemotherapeutics to combat the novel coronavirus which has spread to the whole world due to its contagiousness. In the viral genome exploration, it has been found that the main protease, also known as chymotrypsin-like cysteine protease ([Mpro] or 3C-like protease [3CLpro]) is responsible for the novel coronavirus replication, transcription, and host immunity destruction. Objectives: Therefore, the main protease has been selected as one of the major targets for the design of new inhibitors. The protein crystallographic and molecular docking studies on SARS-CoV-2 Mpro inhibitors and some quantitative structure-activity relationship (QSAR) studies have been carried out on SARSCoV main protease inhibitors to get some lead molecules for SARS-CoV-2 inhibition. However, there is hardly any QSAR done on the diverse data of SARS-CoV-2 main protease inhibitors. In view of it, QSAR studies have been attempted on SARS-CoV-2 Mpro inhibitors utilizing theoretical molecular descriptors solely computed from the structures of novel corona viral main protease inhibitors. Methods: Methods: As the number of structural descriptors is more than the observations, a genetic algorithm coupled with multiple linear methods has been applied for the development of QSAR models taking diverse SARS-CoV-2 Mpro inhibitors. Results: The developed best QSAR model showing R2 , Q2 Loo, and R2 pred values of 0.7389, 0.6666, and 0.6453 respectively has been further validated on an external data set where a good correlation (r = 0.787) has been found. Conclusion: Therefore, this model may be useful for the design of new SARS-CoV-2 main protease inhibitors.

Novel pyrazoline linked acyl thiourea pharmacophores as antimicrobial, urease, amylase and α-glucosidase inhibitors: design, synthesis, SAR and molecular docking studies.

In the present work, a small library of novel pyrazolinyl-acyl thiourea (5a-j) was designed and synthesized through a multistep sequence and the synthesized compounds were screened for their antifungal, antibacterial and antioxidant activities as well as urease, amylase and α-glucosidase inhibitory activities. The synthesized series (5a-o) was characterized using a combination of spectroscopic techniques, including FT-IR, 1H NMR and 13C NMR. All compounds (5a-j) were found to have significant potency against urease, α-glucosidase, α-amylase, and DPPH. The synthesized compounds were also screened for potential antibacterial and anti-fungal inhibition activities. IC50 values for all the prepared compounds for urease, α-glucosidase, amylase, and DPPH inhibition were determined and derivatives 5b and 5g were found to be the most potent urease inhibitors with IC50 values of 54.2 ± 0.32 and 43.6 ± 0.25 μM, respectively. Whilst compound 5b (IC50 = 68.3 ± 0.11 μM) is a potent α-glucosidase inhibitor, compound 5f (90.3 ± 1.08 μM) is a potent amylase inhibitor and compound 5b (103.4 ± 1.15 μM) is a potent antioxidant. The different substitutions on the phenyl ring were the basis for structure-activity relationship (SAR) study. The molecular docking study was performed for the confirmation of binding interactions.

Synthesis and immunogenicity evaluation of oligosaccharide epitopes for the development of a glycoconjugate vaccine against Streptococcus pneumoniae serotype 3

A preliminary structure–activity relationship study revealed the potential ST3 oligosaccharide antigenic epitope for anti-ST3 vaccine development.

Design, synthesis, pharmacological evaluation, and in silico studies of the activity of novel spiro pyrrolo[3,4-d]pyrimidine derivatives.

In the present study, spiro compounds are shown to have distinctive characteristics because of their interesting conformations and their structural impacts on biological systems. A new family of functionalized spiro pyrrolo[3,4-d]pyrimidines is prepared via the one-pot condensation reaction of amino cyclohexane derivatives with benzaldehyde to prepare fused azaspiroundecanedione and azaspirodecenone/thione derivatives. A series of synthesized spiro compounds were scanned against DPPH and evaluated for their ability to inhibit COX-1 and COX-2. All compounds exhibit significant antiinflammatory activity, and they inhibited both COX-1 and COX-2 enzymes with a selectivity index higher than celecoxib as a reference drug. The most powerful and selective COX-2 inhibitor compounds were 11 and 6, with selectivity indices of 175 and 129.21 in comparison to 31.52 of the standard celecoxib. However, candidate 14 showed a very promising antiinflammatory activity with an IC50 of 6.00, while celecoxib had an IC50 of 14.50. Our findings are promising in the area of medicinal chemistry for further optimization of the newly designed and synthesized compounds regarding the discussed structure-activity relationship study (SAR), in order to obtain a superior antioxidant lead compound in the near future. All chemical structures of the novel synthesized candidates were unequivocally elucidated and confirmed utilizing spectroscopic and elemental investigations.

Synthesis, Insecticidal Activities, and Structure-Activity Relationship Studies of Novel Diamide Compounds Containing (Halogenated) Alkoxy Group

Synthesis, Insecticidal Activities, and Structure-Activity Relationship Studies of Novel Diamide Compounds Containing (Halogenated) Alkoxy Group

Structure-activity relationship study of anti-wear additives in rapeseed oil based on machine learning and logistic regression.

Anti-wear performance is a crucial quality of lubricants, and it is important to conduct research into the structure-activity relationship of anti-wear additives in bio-based lubricants. These lubricants are eco-friendly and energy-efficient. A literature review resulted in the construction of a dataset comprising 779 anti-wear properties of 79 anti-wear additives in rapeseed oil, at various loadings and additive levels. The anti-wear additives were classified into six groups, including phosphoric acid, formate esters, borate esters, thiazoles, triazine derivatives, and thiophene. Logistic regression analysis revealed that the quantity and kind of anti-wear agents had significant effects on the anti-wear properties of rapeseed oil, with phosphoric acid being the most effective and thiophene being the least effective. To identify the specific structural data that affect the anti-wear capabilities of additives in bio-based lubricants of rapeseed oil, a random forest classification model was developed. The results showed a 0.964 accuracy (ACC) and a 0.931 Matthews Correlation Coefficient (MCC) on the test set. The ranking of importance and characterization of MACCS descriptors in the model confirms that anti-wear additives with chemical structures containing P, O, N, S and heterocyclic groups, along with more than two methyl groups, improve the anti-wear performance of rapeseed oil. The application of data analysis and machine learning to investigate the classifications and structural characteristics of anti-wear additives in rapeseed oil provides data references and guiding principles for designing anti-wear additives in bio-based lubricants.

New pyrazolylindolin-2-one based coumarin derivatives as anti-melanoma agents: design, synthesis, dual BRAFV600E/VEGFR-2 inhibition, and computational studies.

Malignant melanoma is the most invasive skin cancer with the highest risk of death. The inhibition of BRAFV600E appears relevant for overcoming secondary resistance developed during melanoma treatment. BRAFV600E triggers angiogenesis via modification of the expression of angiogenic inducers, which play a crucial role in the metastasis of melanoma. Accordingly, the dual inhibition of the BRAFV600E/VEGFR-2 signaling pathway is considered a rational approach in the design of anti-melanoma candidates. In this study, a new class of pyrazolylindolin-2-one linked coumarin derivatives as dual BRAFV600E/VEGFR-2 inhibitors targeting A375 melanoma cells was designed. Target compounds were tailored to occupy the pockets of BRAFV600E and VEGFR-2. Most of the synthesized compounds demonstrated potent mean growth inhibitory activity against A375 cells. Compound 4j was the most active cytotoxic derivative, displaying an IC50 value at a low micromolar concentration of 0.96 μM with a significant safety profile. Moreover, 4j showed dual potent inhibitory activity against BRAFV600E and VEGFR-2 (IC50 = 1.033 and 0.64 μM, respectively) and was more active than the reference drug sorafenib. Furthermore, derivative 4j caused significant G0/G1 cell cycle arrest, induced apoptosis, and inhibited the migration of melanoma cells. Molecular docking showed that compound 4j achieved the highest ΔG value of -9.5 kcal mol-1 against BRAFV600E and significant ΔG of -8.47 kcal mol-1 against VEGFR-2. Furthermore, the structure-activity relationship study revealed that TPSA directly contributed to the anticancer activity of the tested compounds.

Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters.

Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca2+ mobilization assay wherein voltage-gated Ca2+ channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories.

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library.

The discovery of novel and highly effective P-gp inhibitors is considered to be an effective strategy for overcoming tumor drug resistance. In this paper, a phenotypic screening via a self-constructed synthetic methodology-based library identified a new class of tricyclic spiroindole derivatives with excellent tumor multidrug resistance reversal activity. A stereospecific compound OY-103-B with the best reversal activity was obtained based on a detailed structure-activity relationship study, metabolic stability optimization and chiral resolution. For the VCR-resistant Eca109 cell line (Eca109/VCR), co-administration of 5.0 μM OY-103-B resulted in a reversal fold of up to 727.2, superior to the typical third-generation P-gp inhibitor tariquidar. Moreover, the compound inhibited the proliferation of Eca109/VCR cells in a concentration-dependent manner in plate cloning and flow cytometry. Furthermore, fluorescence substrate accumulation assay and chemotherapeutic drug reversal activity tests demonstrated that OY-103-B reversed tumor drug resistance via P-gp inhibition. In conclusion, this study provides a novel skeleton that inspires the design of new P-gp inhibitors, laying the foundation for the treatment of drug-resistant tumors.