The thermoelectric properties of bismuth telluride thin film (BTTF) was tuned by inducing internal strain through a combination of combinatorial gradient thermal annealing (COGTAN) and machine learning. BTTFs were synthesized via magnetron sputter coating and then treated by COGTAN. The crystal structure and thermoelectric properties, namely Seebeck coefficient and thermal conductivity, of the treated samples were analyzed via micropoint X-ray diffraction and scanning thermal probe microimaging, respectively. The obtained combinatorial data reveals the correlation between internal strain and the thermoelectric properties. The Seebeck coefficient of BTTF exhibits largest sensitivity, where the value ranges from 7.9 to −108 μV/K. To further explore the possibility to enhance Seebeck coefficient, the combinatorial data were subjected to machine learning. The trained model predicts that optimal strains of 3–4% and 1–2% along the a- and c-axis, respectively, significantly improve Seebeck coefficient. The technique demonstrated herein can be used to predict and enhance the performance of thermoelectric materials by inducing internal strain.

High-throughput X-ray diffraction (XRD) is one of the most indispensable techniques to accelerate materials research. However, the conventional XRD analysis with a large beam spot size may not best appropriate in a case for characterizing organic materials thin film libraries, in which various films prepared under different process conditions are integrated on a single substrate. Here, we demonstrate that high-resolution grazing incident XRD mapping analysis is useful for this purpose: A 2-dimensional organic combinatorial thin film library with the composition and growth temperature varied along the two orthogonal axes was successfully analyzed by using synchrotron microbeam X-ray. Moreover, we show that the time-consuming mapping process is accelerated with the aid of a machine learning technique termed as Bayesian optimization based on Gaussian process regression.

Recent advances in high-throughput experimentation for combinatorial studies have accelerated the discovery and analysis of materials across a wide range of compositions and synthesis conditions. However, many of the more powerful characterization methods are limited by speed, cost, availability, and/or resolution. To make efficient use of these methods, there is value in developing approaches for identifying critical compositions and conditions to be used as a priori knowledge for follow-up characterization with high-precision techniques, such as micrometer-scale synchrotron-based X-ray diffraction (XRD). Here, we demonstrate the use of optical microscopy and reflectance spectroscopy to identify likely phase-change boundaries in thin film libraries. These methods are used to delineate possible metastable phase boundaries following lateral-gradient laser spike annealing (lg-LSA) of oxide materials. The set of boundaries are then compared with definitive determinations of structural transformations obtained using high-resolution XRD. We demonstrate that the optical methods detect more than 95% of the structural transformations in a composition-gradient La-Mn-O library and a Ga2O3 sample, both subject to an extensive set of lg-LSA anneals. Our results provide quantitative support for the value of optically detected transformations as a priori data to guide subsequent structural characterization, ultimately accelerating and enhancing the efficient implementation of micrometer-resolution XRD experiments.

Relative role of enthalpy and entropy in the stabilization of senary FCC Al–Co–Cr–Fe–Ni–Mn high entropy alloys was investigated via a high throughput combinatorial solid-to-solid diffusion couple approach. Many off-equiatomic compositions of FCC AlpCoqCrrFesNitMnu were generated by the diffusing Al and Ni in equiatomic Co20Cr20Fe20Ni20Mn20 alloy, i.e., the Al48Ni52 vs Co20Cr20Fe20Ni20Mn20 diffusion couple, annealed at 900°, 1000°, 1100°, and 1200 °C. Above 1000 °C, the solubility limit of Al in off-equiatomic AlpCoqCrrFesNitMnu alloy was determined to be higher than the solubility limit of Al in equiatomic AlxCoCrFeNiMn alloy. Compositions corresponding to the highest solubility limit of Al in off-equiatomic AlpCoqCrrFesNitMnu alloy exhibited a lower free energy of mixing, i.e., higher thermodynamic stability, than equiatomic AlxCoCrFeNiMn compositions, at 1100 °C and above. Therefore, the role of enthalpy was estimated to be significant in achieving higher thermodynamic stability in off-equiatomic alloys, since they always have lower entropy of mixing than their equiatomic counterparts. The magnitude of interdiffusion coefficients of individual elements in Al–Co–Cr–Fe–Ni–Mn alloys were compared to the interdiffusion coefficients in relevant quinary, quaternary, and ternary solvent-based alloys. Interdiffusion coefficients were not necessarily lower in FCC Al–Co–Cr–Fe–Ni–Mn alloys; therefore no sluggish diffusion was observed in FCC HEA, but diffusion of individual elements in BCC Al–Co–Cr–Fe–Ni–Mn alloy followed the sluggish diffusion hypothesis except for Ni. All compositions in the FCC Al–Co–Cr–Fe–Ni–Mn alloy were observed to comply with existing empirical single phase formation rules in high entropy alloys.

A MoS2-supported-calix[4]arene (MoS2-CA4) nanocatalyst was used for efficient synthesis of 2,4,5-trisubstituted imidazole derivatives from 1-(4-nitrophenyl)-2-(4-(trifluoromethyl)phenyl)ethane-1,2-dione, aldehydes and ammonium acetate under solvent-free conditions. Reusability of the catalyst up to five cycles without any significant loss in the yields of the product is the unique feature of this heterogeneous solid catalysis. Furthermore, the noteworthy highlights of this method are safe reaction profiles, broad substrate scope, excellent yields, economical, solvent-free, and simple workup conditions. All synthesized compounds were evaluated for their in vitro antitubercular (TB) activity against Mycobacterium tuberculosis (Mtb) H37Rv. Among the screened compounds 3c, 3d, 3f, 3m, and 3r had MIC values of 2.15, 2.78, 5.75, 1.36, and 0.75 μM, respectively, and exhibited more potency than the reference drugs pyrazinamide (MIC: 3.12 μM), ciprofloxacin (MIC: 4.73 μM), and ethambutol (7.61 μM). Besides, potent compounds (3c, 3d, 3f, 3m, and 3r) have been tested for inhibition of MabA (β-ketoacyl-ACP reductase) enzyme and cytotoxic activity against mammalian Vero cell line. A molecular docking study was carried out on the MabA (PDB ID: 1UZN) enzyme to predict the interactions of the synthesized compounds. The results of the in vitro anti-TB activity and docking study showed that synthesized compounds have a strong anti-TB activity and can be adapted and produced more effectively as a lead compound.

Electromanipulation and electrical characterization of cancerous cells is becoming a topic of high interest as the results reported to date demonstrate a good differentiation among various types of cells from an electrical viewpoint. Dielectrophoresis and broadband dielectric spectroscopy are complementary tools for sorting, identification, and characterization of malignant cells and were successfully used on both primary tumor cells and culture cells as well. However, the literature is presenting a plethora of studies with respect to electrical evaluation of these type of cells, and this review is reporting a collection of information regarding the functioning principles of different types of dielectrophoresis setups, theory of cancer cell polarization, and electrical investigation (including here the polarization mechanisms). The interpretation of electrical characteristics against frequency is discussed with respect to interfacial/Maxwell–Wagner polarization and the parasitic influence of electrode polarization. Moreover, the electrical equivalent circuits specific to biological cells polarizations are discussed for a good understanding of the cells’ morphology influence. The review also focuses on advantages of specific low-conductivity buffers employed currently for improving the efficiency of dielectrophoresis and provides a set of synthesized data from the literature highlighting clear differentiation between the crossover frequencies of different cancerous cells.

Peptide macrocyclization is typically associated with the development of higher affinity and more protease stable protein ligands, and, as such, is an important tool in peptide drug discovery. Yet, within the context of a diverse library, does cyclization give inherent advantages over linear peptides? Here, we used mRNA display to create a peptide library of diverse ring sizes and topologies (monocyclic, bicyclic, and linear). Several rounds of in vitro selection against streptavidin were performed and the winning peptide sequences were analyzed for their binding affinities and overall topologies. The effect of adding a protease challenge on the enrichment of various peptides was also investigated. Taken together, the selection output yields insights about the relative abundance of binders of various topologies within a structurally diverse library.

An efficient one-pot multicomponent reaction for the synthesis of novel tetrasubstituted hexahydroimidazo[1,2-a]pyridines starting from readily available cinnamaldehydes, ethylenediamines, and 1,3-dicarbonyl compounds catalyzed by AcOH is described. Two new cycles and four new bonds are constructed with all reactants being efficiently utilized in this transformation. The products could be obtained in 1–3 h under ambient conditions exclusively as a single isomer (trans). Single-crystal X-ray analysis confirmed the trans derivative as the only isomer.

We propose to minimize the sampling time for high-throughput measurements of powder X-ray diffraction (XRD) and X-ray absorption fine structure (XAFS) in synchrotron radiation. The conventional synchrotron radiation powder X-ray diffraction method requires filling of a capillary tube, but a structure-refining diffraction pattern could be obtained by transferring the crushed powder to a tape and rotating the cassette-tape tool by ±5° around the sample position. XAFS spectra could also be measured with the sample attached to the tape. The time required for sample preparation was greatly reduced, which made high-throughput experiments with powders in synchrotron radiation experiments more accessible.

Mutagenesis of surface-exposed residues, or “resurfacing”, is a protein engineering strategy that can be utilized to disrupt antibody recognition or modulate the capacity of a protein to elicit antibody responses. We apply resurfacing to engineer Dengue virus envelope protein domain III (DENV DIII) antigens with the goal of focusing humoral recognition on epitopes of interest by selective ablation of irrelevant and undesired epitopes. Cross-reactive but non-neutralizing antibodies have the potential to enhance Dengue virus (DENV) infection by a process called antibody-dependent enhancement, thought to be associated with severe secondary heterotypic infection. Thus, a focus on epitopes associated with broadly neutralizing antibodies is important both for understanding human antibody responses against DENV and for the development of a successful DENV vaccine. To engineer DENV DIII antigens focusing on the AG strand epitope associated with broadly neutralizing antibody responses, we generated yeast surface display libraries of DENV2 DIII where the AB loop (associated with cross-reactive but non-neutralizing antibody responses) and FG loop (associated with serotype-specific antibody responses) were mutagenized to allow for all possible amino acid substitutions. Loop variants that maintained the AG strand epitope and simultaneously disrupted the AB and FG loop epitopes exhibited high and diverse mutational loads that were amenable to loop exchange and transplantation into a DENV4 DIII background. Thus, several loop variants fulfill this antigenicity criteria regardless of serotype context. The resulting resurfaced DIII antigens may be utilized as AG strand epitope-focusing probes or immunogen candidates.

The correlation between the crystal structure and valence band structure of a (GaxIn1–x)2O3 solid solution system was investigated by using combinatorial synthesis. At a low Ga content of (GaxIn1–x)2O3 with a single-phase cubic In2O3 crystal structure, a surface electron accumulation layer (SEAL), which is an important electrical phenomenon in In2O3, was confirmed. When the Ga content increased to approximately x = 0.4, mixed crystal structures of Ga2O3 and In2O3 were produced. Above x = 0.5, the dominant valence band structure was attributed to Ga2O3, the SEAL disappeared, and the sheet resistance increased greatly by 5 orders of magnitude or more. The in-gap state and valence band structure of the (GaxIn1–x)2O3 solid solution system were strongly affected by Ga2O3; however, the valence band maximum position shifted to a higher binding energy.

Fourteen (hetero-)(arylidene)arylhydrazide derivatives (ABH1–ABH14) were synthesized, and their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) were evaluated. Compound ABH5 most potently inhibited MAO-B with an IC50 value of 0.025 ± 0.0019 μM; ABH2 and ABH3 exhibited high IC50 values as well. Most of the compounds weakly inhibited MAO-A, except ABH5 (IC50 = 3.31 ± 0.41 μM). Among the active compounds, ABH2 showed the highest selectivity index (SI) of 174 for MAO-B, followed by ABH5 (SI = 132). ABH3 and ABH5 effectively inhibited AChE with IC50 values of 15.7 ± 6.52 and 16.5 ± 7.29 μM, respectively, whereas the other compounds were weak inhibitors of AChE. ABH5 was shown to be a reversible competitive inhibitor for MAO-A and MAO-B with Ki values of 0.96 ± 0.19 and 0.024 ± 0.0077 μM, respectively, suggesting that this molecule can be considered as an interesting candidate for further development as a multitarget inhibitor relating to neurodegenerative disorders.

This is the final issue of ACS Combinatorial Science. I write these words with a profound sense of gratitude to the many authors and reviewers who have contributed to its pages, to our Editorial Advisory Board members who have provided wise counsel, and to the small but mighty group of associate editors and staff who have made the journal a joy to put together. I also write with both sadness and confidence at the literal and figurative turning of the page that the journal’s closing represents. Volume 1 of the Journal of Combinatorial Chemistry appeared on Jan. 12, 1999, under the direction of Founding Editor-in-Chief Anthony W. Czarnik. Tony was involved in the combi-chem revolution from its earliest days, when the idea of making and testing libraries of potential small-molecule drugs was new, and the nascent field was dominated by concerns about how parallel synthesis could be done and how compounds could be adequately characterized. New instruments for parallel reactions and purifications were all the rage, new ideas for molecular tagging or bead sorting were eagerly traded at meetings, and companies were founded and folded at a dizzying pace. But the heart of the Journal of Combinatorial Chemistry was always the chemistry: good reactions discovered and optimized for the synthesis of potentially useful molecular structures. The potential power of the field, at least to those moving into it, was obvious. For the most part, I shall not cite particular papers here, for fear of leaving out countless worthy contributions. But, for me, a 1996 review(1) by Wayne Guida and colleagues was critical to my appreciation of the subject. It posed the startling hypothesis that the potential size of the ultimate library of drug-like molecules was essentially infinite, estimated at up to 1063 distinct structures. This suggested that there must be a very large number of chemical answers to every question in any field that relied on molecular structure and properties. How to find some of those answers became a motivating concern for a substantial number of investigators, and the field of combinatorial chemistry was born. I succeeded Dr. Czarnik as Editor-in-Chief in late 2010, understanding that the field of drug discovery had undergone a revolution with the rollout of the first monoclonal antibody blockbuster, Humira (adalimumab). Antibodies are made by combinatorial synthesis and screening, whether by the immune system or by the laboratory investigator using techniques such as phage display. In appreciation of this, and a parallel understanding that the properties of polymeric materials and other systems of interacting molecular components were being developed by new methods of synthesis and analysis, the ACS agreed to change the name of the journal to ACS Combinatorial Science. As we wrote then, “The name change signals an expansion of the journal’s scope to include combinatorial and evolutionary approaches to problems in biology, molecular biology, materials science, and catalysis development, in addition to the journal’s traditional focus on synthetic chemistry methods and high-throughput drug discovery.” And we were off on a very interesting ride. ACS Combinatorial Science was the first and only ACS journal to be devoted to a way of doing science, rather than to a specific field of knowledge or application. It was perhaps, therefore, destined to be transient, since methods change. It is now undeniable that combinatorial approaches are woven deeply into the fabric of modern therapeutic development. Few companies pursuing a new small-molecule drug would think twice about making a candidate library to probe structure–activity relationships in a scaffold family, and every biotech startup, or academic laboratory in chemical biology for that matter, has at its fingertips powerful tools for generating and testing biomolecular libraries of immense size. The fields that use solid-state and polymeric materials, from photoelectronics to hydrogels to nanotechnology, now have at their disposal well-accepted methods of making and testing candidates of varying composition. New analytical methods have always been a vital part of combinatorial exploration, and these are now widely distributed and ever improving. Thus, at least the initial development of combinatorial molecular science and technology may be considered complete. Its impact has been profound, and its methods will continue to shape our world and help answer society’s most critical challenges. New chemistry will always infuse library synthesis and materials development. Biomolecular evolution will continue to grow in power and sophistication. And new excitement in such areas as machine learning and DNA-encoded libraries will continue to appear. I will look for all of these in the pages of other journals that cover an enormous range of subjects. And I commend all of you readers of this journal to many happy interactions in the combinatorial enterprise that is research itself and to the insights and discoveries that emerge from them. Views expressed in this editorial are those of the author and not necessarily the views of the ACS. This article references 1 other publications.

New 8-chloro-2-phenyl-2,7-naphthyridin-1(2H)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based N-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2H)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, 17c (IC50,MET of 13.8 nM) or 17e (IC50,AXl of 17.2 nM) and 17i (IC50,AXl of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.

N-Isocyaniminotriphenylphosphorane (NIITP) is a functionalized isonitrile that has been extensively applied in a variety of organic reactions during the last two decades. This Review summarizes the most important applications in organic synthesis of this versatile reactant, with the focus posed on mechanistic and methodological aspects allowing the generation of molecular diversity. NIITP combines the reactivity of isonitriles with that of phosphoranes to enable chemical transformations employed in the construction of compound libraries. Here, we cover from the initial applications of NIITP in the Nef isocyanide reaction to further derivations that render a variety of heterocyclic scaffolds. The presence of the isonitrile moiety in this singular compound makes possible the double addition of nucleophiles and electrophiles, which followed by inter(intra)molecular aza-Wittig type transformations enable several multicomponent and tandem processes. In particular, we stress the impact of NIITP in oxadiazole chemistry, from the early two-component transformations to recent examples of multicomponent reactions that take place in the presence of suitable electrophiles. In addition, we briefly describe the role of NIITP chemistry in generating skeletal and conformational diversity in cyclic peptides. The reaction of NIITP with alkynes is thoroughly revised, with particular emphasis on silver-catalyzed processes that have been developed in the last years. Biomedicinal applications of some reaction products are also mentioned along with a perspective of future applications of this reactant.

The current COVID-19 pandemic caused by a novel coronavirus SARS-CoV-2 urgently calls for a working therapeutic. Here, we report a computation-based workflow for efficiently selecting a subset of FDA-approved drugs that can potentially bind to the SARS-CoV-2 main protease MPRO. The workflow started with docking (using Autodock Vina) each of 1615 FDA-approved drugs to the MPRO active site. This step selected 62 candidates with docking energies lower than −8.5 kcal/mol. Then, the 62 docked protein–drug complexes were subjected to 100 ns of molecular dynamics (MD) simulations in a molecular mechanics (MM) force field (CHARMM36). This step reduced the candidate pool to 26, based on the root-mean-square-deviations (RMSDs) of the drug molecules in the trajectories. Finally, we modeled the 26 drug molecules by a pseudoquantum mechanical (ANI) force field and ran 5 ns hybrid ANI/MM MD simulations of the 26 protein–drug complexes. ANI was trained by neural network models on quantum mechanical density functional theory (wB97X/6-31G(d)) data points. An RMSD cutoff winnowed down the pool to 12, and free energy analysis (MM/PBSA) produced the final selection of 9 drugs: dihydroergotamine, midostaurin, ziprasidone, etoposide, apixaban, fluorescein, tadalafil, rolapitant, and palbociclib. Of these, three are found to be active in literature reports of experimental studies. To provide physical insight into their mechanism of action, the interactions of the drug molecules with the protein are presented as 2D-interaction maps. These findings and mappings of drug–protein interactions may be potentially used to guide rational drug discovery against COVID-19.

Thin films of two types of high-entropy oxides (HEOs) have been deposited on 76.2 mm Si wafers using combinatorial sputter deposition. In one type of the oxides, (MgZnMnCoNi)Ox, all the metals have a stable divalent oxidation state and similar cationic radii. In the second type of oxides, (CrFeMnCoNi)Ox, the metals are more diverse in the atomic radius and valence state, and have good solubility in their sub-binary and ternary oxide systems. The resulting HEO thin films were characterized using several high-throughput analytical techniques. The microstructure, composition, and electrical conductivity obtained on defined grid maps were obtained for the first time across large compositional ranges. The crystalline structure of the films was observed as a function of the metallic elements in the composition spreads, that is, the Mn and Zn in (MgZnMnCoNi)Ox and Mn and Ni in (CrFeMnCoNi)Ox. The (MgZnMnCoNi)Ox sample was observed to form two-phase structures, except single spinel structure was found in (MgZnMnCoNi)Ox over a range of Mn > 12 at. % and Zn < 44 at. %, while (CrFeMnCoNi)Ox was always observed to form two-phase structures. Composition-controlled crystalline structure is not only experimentally demonstrated but also supported by density function theory calculation.

A new coronavirus (CoV) caused a pandemic named COVID-19, which has become a global health care emergency in the present time. The virus is referred to as SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) and has a genome similar (∼82%) to that of the previously known SARS-CoV (SARS coronavirus). An attractive therapeutic target for CoVs is the main protease (Mpro) or 3-chymotrypsin-like cysteine protease (3CLpro), as this enzyme plays a key role in polyprotein processing and is active in a dimeric form. Further, Mpro is highly conserved among various CoVs, and a mutation in Mpro is often lethal to the virus. Thus, drugs targeting the Mpro enzyme significantly reduce the risk of mutation-mediated drug resistance and display broad-spectrum antiviral activity. The combinatorial design of peptide-based inhibitors targeting the dimerization of SARS-CoV Mpro represents a potential therapeutic strategy. In this regard, we have compiled the literature reports highlighting the effect of mutations and N-terminal deletion of residues of SARS-CoV Mpro on its dimerization and, thus, catalytic activity. We believe that the present review will stimulate research in this less explored yet quite significant area. The effect of the COVID-19 epidemic and the possibility of future CoV outbreaks strongly emphasize the urgent need for the design and development of potent antiviral agents against CoV infections.

Thin-film continuous composition spreads of Fe–Co–O were fabricated by reactive cosputtering from elemental Fe and Co targets in reactive Ar/O2 atmosphere using deposition temperatures ranging from 300 to 700 °C. Fused silica and platinized Si/SiO2 strips were used as substrates. Ti and Ta were investigated as adhesion layer for Pt and the fabrication of the Fe–Co–O films. The thin-film composition spreads were characterized by high-throughput electron-dispersive X-ray spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, atomic force microscopy, scanning electron microscopy, and optical transmission spectroscopy. The Fe-content ranged from 28 to 72 at. %. The spinel phases Fe2CoO4 and FeCo2O4 could be synthesized and stabilized at all deposition temperatures with a continuous variation in spinel composition in between. The dependence of the film surface microstructure on the deposition temperature and the composition was mapped. Moreover, the band gap values, ranging from 2.41 eV for FeCo2O4 to 2.74 eV for Fe2CoO4, show a continuous variation with the composition.

Combinatorial synthesis and high-throughput characterization of thin-film materials libraries enable to efficiently identify both photoelectrochemically active and inactive, as well as stable and instable systems for solar water splitting. This is shown on six ternary metal vanadate (M–V–O, M = Cu, Ag, W, Cr, Co, Fe) thin-film materials libraries, fabricated using combinatorial reactive magnetron cosputtering with subsequent annealing in air. By means of high-throughput characterization of these libraries correlations between composition, crystal structure, photocurrent density, and stability of the M–V–O systems in different electrolytes such as acidic, neutral and alkaline media were identified. The systems Cu–V–O and Ag–V–O are stable in alkaline electrolyte and exhibited photocurrents of 170 and 554 μA/cm2, respectively, whereas the systems W–V–O, Cr–V–O, and Co–V–O are not stable in alkaline electrolyte. However, the Cr–V–O and Co–V–O systems showed an enlarged photoactive region in acidic electrolyte, albeit with very low photocurrents (<10 μA/cm2). Complete data sets obtained from these different screening sets, including information on nonpromising systems, lays groundwork for their use to predict new systems for solar water splitting, for example, by machine learning.