Analog Design Research Articles

Design, Synthesis and Antifungal Activities of Novel Pyrazole Analogues Containing the Aryl Trifluoromethoxy Group.

On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF3 were designed and synthesized. Their chemical structures were characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 μg/mL. Compounds 1t and 1v exhibited higher activity against all the tested fungi, and 1v displayed the highest activity against F. graminearum with an EC50 value of 0.0530 μM, which was comparable with commercial pyraclostrobin. Structure-activity relationship analysis showed that, with respect to the R1 substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R2 substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents.

Understanding the Impact of Extension Region on Stacked Nanosheet FET: Analog Design Perspective

This work incorporates an in-depth physics-based investigation of Nanosheet FET’s (NSFET’s) extension region for analog circuit design. When extension length (LEXT) is changed from 8 nm to 3 nm, the NSFET exhibits an increment in IOFF (∼8×) and subthreshold swing ‘SS’ (∼5mV/dec), with a ∼1.5× enhancement in ION. Though driving capacity does not increase proportionally on stacking the sheets owing to the location of contacts, however the ION/IOFF ratio increases by ∼ 10× on stacking two more sheets. A common source (CS) amplifier is utilized for the analysis of the circuit-level performance. The gain-bandwidth profile is worth highlighting that the extension region gives feasibility to modulate the gain and bandwidth of the amplifier as compared to sheet stacking. It is investigated that a higher extension length (8 nm) gives a ∼27% higher gain, while a lower LEXT (3 nm) gives ∼2× higher bandwidth. Though sheet stacking increases the ON current, it does not significantly impact the gain, bandwidth, or phase shift.

Development of Shortened miR-506-3p Mimics Exhibiting Strong Differentiation-Inducing Activity in Neuroblastoma Cells.

microRNA mimics are synthetic RNA molecules that imitate the mature miRNA duplexes and their functions. These mimics have shown promise in treating cancers. Nucleotide chemical modifications of microRNA mimics have been investigated and have improved the stability of miRNA mimics. However, the potential therapeutic benefit of mimic analogs based on sequence modifications has not been explored. miR-506-3p was identified as a differentiation-inducing microRNA in neuroblastoma cells, suggesting the potential of applying the miR-506-3p mimic in neuroblastoma differentiation therapy. In this study, we explored the possibility of developing shortened miR-506-3p analogs that can maintain differentiation-inducing activities comparable to the wild-type miR-506-3p mimic. We found that deleting up to two nucleotides at either the 3' end or within the middle region of the miR-506-3p sequence fully maintained the differentiation-inducing activity when compared to the wild-type mimic. Deleting up to four nucleotides from the 3' end or deleting three nucleotides in the middle positions diminished the differentiation-inducing activity, but the analogs still maintained differentiation-inducing activities that were significantly higher than the negative control oligo. The shortened analog designs potentially benefit patients from two perspectives: (1) the reduced cost of manufacturing shortened analogs, and (2) the reduced non-specific toxicity due to their smaller molecular sizes.

Molecular recognition of trehalose and trehalose analogues by Mycobacterium tuberculosis LpqY-SugABC

Trehalose plays a crucial role in the survival and virulence of the deadly human pathogen Mycobacterium tuberculosis (Mtb). The type I ATP-binding cassette (ABC) transporter LpqY-SugABC is the sole pathway for trehalose to enter Mtb. The substrate-binding protein, LpqY, which forms a stable complex with the translocator SugABC, recognizes and captures trehalose and its analogues in the periplasmic space, but the precise molecular mechanism for this process is still not well understood. This study reports a 3.02-Å cryoelectron microscopy structure of trehalose-bound Mtb LpqY-SugABC in the pretranslocation state, a crystal structure of Mtb LpqY in a closed form with trehalose bound and five crystal structures of Mtb LpqY in complex with different trehalose analogues. These structures, accompanied by substrate-stimulated ATPase activity data, reveal how LpqY recognizes and binds trehalose and its analogues, and highlight the flexibility in the substrate binding pocket of LpqY. These data provide critical insights into the design of trehalose analogues that could serve as potential molecular probe tools or as anti-TB drugs.

Design, synthesis, anti-inflammatory evaluation, and molecular modelling of new coumarin-based analogs combined curcumin and other heterocycles as potential TNF-α production inhibitors via upregulating Nrf2/HO-1, downregulating AKT/mTOR signalling pathways and downregulating NF-κB in LPS induced macrophages

Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC50 value of 5.32 μM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kβ, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.

GENERA: A Combined Genetic/Deep-Learning Algorithm for Multiobjective Target-Oriented De Novo Design.

This study introduces a new de novo design algorithm called GENERA that combines the capabilities of a deep-learning algorithm for automated drug-like analogue design, called DeLA-Drug, with a genetic algorithm for generating molecules with desired target-oriented properties. Specifically, GENERA was applied to the angiotensin-converting enzyme 2 (ACE2) target, which is implicated in many pathological conditions, including COVID-19. The ability of GENERA to de novo design promising candidates for a specific target was assessed using two docking programs, PLANTS and GLIDE. A fitness function based on the Pareto dominance resulting from computed PLANTS and GLIDE scores was applied to demonstrate the algorithm's ability to perform multiobjective optimizations effectively. GENERA can quickly generate focused libraries that produce better scores compared to a starting set of known ACE-2 binders. This study is the first to utilize a DL-based algorithm designed for analogue generation as a mutational operator within a GA framework, representing an innovative approach to target-oriented de novo design.

Germacrone, a novel and safe anticancer agent from genus curcuma : a review of its mechanism.

Germacrone, a kind of natural sesquiterpenoid compound, has been reported to exhibit many pharmacological properties, especially the anticancer effect. Many in vitro experiments have been performed on various cancer cell lines, trying to explore their anticancer mechanism. Aiming at investigating the anticancer effect of germacrone, this article reviews the extant information on existing literature about germacrone-related studies. The anticancer mechanisms and clinical usages of germacrone are summarized. Literature databases (such as PubMed and CNKI) are used to search the current studies and experimental research about the anticancer effect information of germacrone. Anticancer mechanism of germacrone includes cell cycle arrest inducing, programmed cell death (apoptosis, autophagy, pyroptosis and ferroptosis) inducing, and estrogen-related genes mediating. Structural modification and analogue design are worthy of further study in the future.

Design, synthesis and biological evaluation of novel oxindole analogs as antitubercular agents.

Aim: To design, synthesize and evaluate oxindole derivatives for antitubercular activity. Methodology: We synthesized the derivatives, confirmed their structures by 1H/13C NMR and mass spectrometry, and evaluated them for antitubercular activity against Mycobacterium tuberculosis H37Rv strain using the microplate alamarBlue™ assay. Results: Among all the synthesized derivatives, OXN-1, -3 and -7 exhibited excellent antitubercular activity (minimum inhibitory concentration [MIC]: 0.78μg/ml). Compounds with a MIC ≤1.56 were tested for cytotoxicity against human embryonic kidney cells and were found to be relatively nontoxic. Molecular docking analysis of OXN-1, -3 and -7 was performed to determine their binding patterns at the active site of DNA topoisomerase II (PDB-5BS8). In drug combination studies, OXN-1, 3 and 7 showed synergism with isoniazid. Conclusion: The obtained results reveal that oxindole derivatives exhibit potent antitubercular activity.

Magnetic Resonance Safety Evaluation of a Novel Alumina Matrix Composite Ceramic Knee and Image Artifact Comparison to a Metal Knee Implant of Analogous Design.

Image artifacts caused by metal knee implants in 1.5T and 3T magnetic resonance imaging (MRI) systems complicate imaging-based diagnosis of the peri-implant region after total knee arthroplasty. Alternatively, metal-free knee prostheses could effectively minimize MRI safety hazards and offer the potential for higher quality diagnostic images. A novel knee arthroplasty device composed of BIOLOX delta, an alumina matrix composite (AMC) ceramic, was tested in a magnetic resonance (MR) environment. American Society for Testing and Materials test methods were used for evaluating magnetically induced displacement force, magnetically induced torque, radiofrequency-induced heating, and MR image artifact. Magnetically induced displacement force and magnetically induced torque results of the AMC ceramic knee indicated that these effects do not pose a known risk in a clinical MR environment, as assessed in a 3T magnetic field. Moreover, minimal radiofrequency-induced heating of the device was observed. In addition, the AMC ceramic knee demonstrated minimal MR image artifacts (7 mm) in comparison to a cobalt-chromium knee (88 mm). The extremely low magnetic susceptibility of AMC (2 ppm) underlines that it is a nonmetallic and nonmagnetic material well suited for the manufacturing of MR Safe orthopaedic implants. The AMC ceramic knee is a novel metal-free total knee arthroplasty device that can be regarded as MR Safe, as suggested by the absence of hazards from the exposure of this implant to a MR environment. The AMC ceramic knee presents the advantage of being scanned with superior imaging results in 3T MRI systems compared to alternative metal implants on the market.

Programmable Energy-Efficient Analog Multilayer Perceptron Architecture Suitable for Future Expansion to Hardware Accelerators

A programmable, energy-efficient analog hardware implementation of a multilayer perceptron (MLP) is presented featuring a highly programmable system that offers the user the capability to create an MLP neural network hardware design within the available framework. In addition to programmability, this implementation provides energy-efficient operation via analog/mixed-signal design. The configurable system is made up of 12 neurons and is fabricated in a standard 130 nm CMOS process occupying approximately 1 mm2 of on-chip area. The system architecture is analyzed in several different configurations with each achieving a power efficiency of greater than 1 tera-operations per watt. This work offers an energy-efficient and scalable alternative to digital configurable neural networks that can be built upon to create larger networks capable of standard machine learning applications, such as image and text classification. This research details a programmable hardware implementation of an MLP that achieves a peak power efficiency of 5.23 tera-operations per watt while consuming considerably less power than comparable digital and analog designs. This paper describes circuit elements that can readily be scaled up at the system level to create a larger neural network architecture capable of improved energy efficiency.

Design of Protegrin-1 Analogs with Improved Antibacterial Selectivity.

Protegrin-1 (PG-1) is a cationic β-hairpin pore-forming antimicrobial peptide having a membranolytic mechanism of action. It possesses in vitro a potent antimicrobial activity against a panel of clinically relevant MDR ESKAPE pathogens. However, its extremely high hemolytic activity and cytotoxicity toward mammalian cells prevent the further development of the protegrin-based antibiotic for systemic administration. In this study, we rationally modulated the PG-1 charge and hydrophobicity by substituting selected residues in the central β-sheet region of PG-1 to design its analogs, which retain a high antimicrobial activity but have a reduced toxicity toward mammalian cells. In this work, eight PG-1 analogs with single amino acid substitutions and five analogs with double substitutions were obtained. These analogs were produced as thioredoxin fusions in Escherichia coli. It was shown that a significant reduction in hemolytic activity without any loss of antimicrobial activity could be achieved by a single amino acid substitution, V16R in the C-terminal β-strand, which is responsible for the PG-1 oligomerization. As the result, a selective analog with a ≥30-fold improved therapeutic index was obtained. FTIR spectroscopy analysis of analog, [V16R], revealed that the peptide is unable to form oligomeric structures in a membrane-mimicking environment, in contrast to wild-type PG-1. Analog [V16R] showed a reasonable efficacy in septicemia infection mice model as a systemic antibiotic and could be considered as a promising lead for further drug design.

Rotamer-Controlled Dual Emissive α-Amino Acids.

The synthesis and photoluminescent properties of novel α-amino acids are described in which the biaryl benzotriazinone-containing chromophores were found to display dual emission fluorescence via locally excited (LE) and twisted intramolecular charge transfer (TICT) states. The intensity of each emission band could be controlled by the electronics and position of the substituents, and this led to the design of a 2-methoxyphenyl analogue that, due to twisting, displayed bright TICT fluorescence, solvatochromism, and pH sensitivity.

Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites.

Mitragynine pseudoindoxyl, a kratom metabolite, has attracted increasing attention due to its favorable side effect profile as compared to conventional opioids. Herein, we describe the first enantioselective and scalable total synthesis of this natural product and its epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro-5-5-6-tricyclic system of these alkaloids was formed through a protecting-group-free cascade relay process in which oxidized tryptamine and secologanin analogues were used. Furthermore, we discovered that mitragynine pseudoindoxyl acts not as a single molecular entity but as a dynamic ensemble of stereoisomers in protic environments; thus, it exhibits structural plasticity in biological systems. Accordingly, these synthetic, structural, and biological studies provide a basis for the planned design of mitragynine pseudoindoxyl analogues, which can guide the development of next-generation analgesics.

Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites**

AbstractMitragynine pseudoindoxyl, a kratom metabolite, has attracted increasing attention due to its favorable side effect profile as compared to conventional opioids. Herein, we describe the first enantioselective and scalable total synthesis of this natural product and its epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro‐5‐5‐6‐tricyclic system of these alkaloids was formed through a protecting‐group‐free cascade relay process in which oxidized tryptamine and secologanin analogues were used. Furthermore, we discovered that mitragynine pseudoindoxyl acts not as a single molecular entity but as a dynamic ensemble of stereoisomers in protic environments; thus, it exhibits structural plasticity in biological systems. Accordingly, these synthetic, structural, and biological studies provide a basis for the planned design of mitragynine pseudoindoxyl analogues, which can guide the development of next‐generation analgesics.

Structure-based design of novel heterocycle-substituted ATDP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility

Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66 (SI = 2019.80, S = 1.9 μg/mL), a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity. Evidently, the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility (SI = 12,497.73, S = 4472 μg/mL) in comparison with ZLM-66 (SI = 2019.80, S = 1.9 μg/mL). This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains (K103N, L100I, Y181C, E138K, and K103N + Y181C). The analog also demonstrated favorable safety and pharmacokinetic profiles, as evidenced by its insensitivity to CYP and hERG, lack of mortality and pathological damage, and good oral bioavailability in rats (F = 27.1%). Further development of 7w for HIV therapy will be facilitated by this valuable information.

Chromone Containing Hybrid Analogues: Synthesis and Applications in Medicinal Chemistry.

The use of privileged scaffolds has proven beneficial for generating novel bioactive scaffolds in drug discovery program. Chromone is one such privileged scaffold that has been exploited for designing pharmacologically active analogues. The molecular hybridization technique combines the pharmacophoric features of two or more bioactive compounds to avail a better pharmacological activity in the resultant hybrid analogues. The current review summarizes the rationale and techniques involved in developing hybrid analogues of chromone, which show potential in fields of obesity, diabetes, cancer, Alzheimer's disease and microbial infections. Here the molecular hybrids of chromone with various pharmacologically active analogues or fragments (donepezil, tacrine, pyrimidines, azoles, furanchalcones, hydrazones, quinolines, etc.) are discussed with their structure-activity relationship against above-mentioned diseases. Detailed methodologies for the synthesis of corresponding hybrid analogues have also been described, with suitable synthetic schemes. The current review will shed light on various strategies utilized for the design of hybrid analogues in the field of drug discovery. The importance of hybrid analogues in various disease conditions is also illustrated. Keywords: Bioactive scaffolds, chromone, drug discovery, molecular hybridization, hybrid analogues.

Structure-Activity Relationships of Triphenylethylene Derivatives and Their Evaluation as Anticancer and Antiviral Agents.

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) that is used in the treatment of breast cancer, yet with the risk of developing uterine cancer. A perfect SERM would act as an estrogen activator on bones, the cardiovascular system, and the central nervous system while providing neutral or estrogen blocking effects on the breast and the uterus. Herein, we report on the design, synthesis, and evaluation of new rigid and flexible TAM analogues. Mainly, a chloro substituent is introduced at the para position of the TAM ring C blocking the CYP2D6 hydroxylation site. Most compounds showed estrogenic activity higher than TAM using the yeast estrogen screen assays, indicating the determinant role of the chloro substituent upon functional activity. Despite being estrogenic, compound 2B showed potent antiproliferative activity in the NCI 60 cell lines with mean GI50 = 3.67 μM, GI50 = 1.05 μM on MCF-7 cell lines, and GI50 = 1.30 μM on MDA-MB-231. The estrogenic activity of compound 2B was further confirmed by stimulating alkaline phosphatase in Ishikawa cells, and it showed no increase in relative uterine wet weight in ovariectomized rats. Compound 2F showed EC90 = 0.31 μg/mL and SI90 = 60 against Ebola virus; this is 200-fold more potent than the positive control favipiravir. This is the first time to report estrogenic triphenylethylenes as anti-EBOV agents. The anti-EBOV activity reported is a function of the substitution pattern of the scaffold rather than the functional activity. Moreover, compound 3D showed excellent PO pharmacokinetic properties in mice. In conclusion, for this class of TAM-like compounds, the blockage of the p-position of ring C is decisive for the functional activity; meanwhile, the triarylethylene substitution pattern is detrimental for the antiviral activity.

Design, synthesis, and antitumor activity of novel oleanolic acid analogues targeting EGFR

Based on the simulated docking of Epidermal growth factor receptor inhibitors with known active small molecule compounds, computer-aided drug design technology was used to analyze key amino acid fragments and determine the active groups binding with key sites. Then, twelve novel analogues of oleanolic acid (OA) were synthesized by introducing active groups at the C-3 and C-28 positions of OA. The structures of these novel analogues were confirmed by NMR and MS. Furthermore, the antitumor activities of these novel analogues were evaluated by MTT assay. As a result, compounds I3 and II3 showed stronger cytotoxicity on tumor cells than positive controls. In conclusion, our study synthesized twelve novel analogues of OA and determined compounds I3 and II3 had better antitumor effect, which may be potential candidate compounds for tumor therapy.

Pretraining Graph Neural Networks for Few-Shot Analog Circuit Modeling and Design

Being able to predict the performance of circuits without running expensive simulations is a desired capability that can catalyze automated design. In this paper, we present a supervised pretraining approach to learn circuit representations that can be adapted to new circuit topologies or unseen prediction tasks. We hypothesize that if we train a neural network (NN) that can predict the output direct current (DC) voltages of a wide range of circuit instances it will be forced to learn generalizable knowledge about the role of each circuit element and how they interact with each other. The dataset for this supervised learning objective can be easily collected at scale since the required DC simulation to get ground truth labels is relatively cheap. This representation would then be helpful for few-shot generalization to unseen circuit metrics that require more time consuming simulations for obtaining the ground-truth labels. To cope with the variable topological structure of different circuits we describe each circuit as a graph and use graph neural networks (GNNs) to learn node embeddings. We show that pretraining GNNs on prediction of output node voltages can encourage learning representations that can be adapted to new unseen topologies or prediction of new circuit level properties with up to 10x more sample efficiency compared to a randomly initialized model. We further show that we can improve sample efficiency of prior SoTA model-based optimization methods by 2x (almost as good as using an oracle model) via fintuning pretrained GNNs as the feature extractor of the learned models.

Improvements to Statistical Characterization and Modeling, and a Caution to be Aware of Spurious Correlation in Statistical Simulation

This paper presents two improvements to, and a warning about a previously unrecognized issue with, statistical modeling, characterization, and simulation. We focus on mismatch, which is key for analog IC design, but the topics addressed are generic. For relative variation (i.e., % difference), we show that conventional measures have significant issues when the variation is large. We present two new measures of % difference between y2 and y1 and show that 100∙ln(y2/y1) is the only measure that is physically correct for mismatch. We review existing, but not widely known, robust alternatives to the textbook approach to estimate standard deviation, show the limitations of these, and propose a new method that is intermediate between, and overcomes limitations of, the textbook and robust approaches. We then show how the accuracy of mismatch simulation, critical for analog IC design, is affected by “spurious correlation” between statistical samples; we are not aware that the importance of this has been recognized previously.