Terpyridyl-Imidazole Based Ligand Coordinated to Ln(Hexafluoroacetyl acetonate)3 Core: Synthesis, Structural Characterization, Luminescence Properties, and Thermosensing Behaviors in Solution and PMMA Film.

A new array of ternary lanthanide complexes of the form [Ln(hfa)3(tpy-HImzphen)] have been synthesized and thoroughly characterized wherein Ln = LaIII (1), EuIII (2), SmIII (3), and TbIII (4); hfa = hexafluoroacetylacetonate; and tpy-HImzphen = 2-(4-[2,2':6',2″]terpyridin-4'-yl-phenyl)-1H-phenanthro[9,10-d]imidazole. Incorporation of tpy-HImzphen onto the Ln-hfa moiety induced a bathochromic shift of the absorption window of the complexes into the visible region. Extensive investigations of the luminescence characteristics have been conducted both at RT and at 77 K to understand the deactivation pathways of the complexes. Both steady-state and time-resolved emission spectral behaviors indicate four distinctive behaviors upon incorporation of tpy-HImzphen onto the lanthanide core, viz., a huge red-shift of the ligand-centered peak for LaIII; almost complete energy transfer for EuIII; very little energy transfer for SmIII, while reverse energy transfer in the case of TbIII. In addition, the EuIII-complex exhibits its excellence in luminescence thermometry in the solution state as well as in poly(methyl methacrylate) (PMMA) thin films. The thermosensitive luminescence response in solution was further utilized to mimic set-reset flip-flop logic operation. A plausible energy transfer scheme has been devised to explain dissimilar luminescence behaviors in the complexes. The role of LMCT was also considered for the observed thermosensing property of the Eu(III) complex.

Perspectives From the RadDiscord Annual Survey: Overview of the Top Study Tools and Evaluation of Study Time and Various Resources.

RATIONALE AND OBJECTIVES: Each year, senior radiology residents take the American Board of Radiology Qualifying (Core) exam to evaluate competency. Approximately 10% of first-time examinees will fail this exam (1). Understanding factors that contribute to success will help residency program directors and trainees prepare for future exams. RadDiscord (www.raddiscord.org), an international radiology educational community, is in the unique position to evaluate different study materials and resources. The goal of this paper is to report the results from the RadDiscord survey and analyze the factors that correlate with higher exam performance and passing. MATERIALS AND METHODS: Following the February 2021, June 2021, and June 2022 exams, RadDiscord members were provided an anonymous survey, collecting information on study resources and exam scores. The collected data were analyzed using various statistical methods. Both descriptive and inferential analyses were performed. RESULTS: A total of 318 residents responded (95% passed). Significant variability in Qualifying (Core) exam performance and perceived quality of internal didactics existed between program types. Residents who did less than 2000 practice questions performed lower on the exam. The Diagnostic Radiology In-Training (DXIT) exam was the most predictive for passing and performance. Qualifying (Core) exam performance negatively correlated with study time, though certain residents did receive some benefit from study time. CONCLUSION: Many factors correlate with passing and Qualifying (Core) exam performance. Residency programs with fewer resources should consider alternative ways to support residents beyond offering study time. Residents who complete at least 2000 practice questions are more likely to pass and DXIT results can be a useful gauge to identify exam readiness.

A terpyridyl-imidazole based europium tris-(ß-diketonate) complex as an efficient molecular luminescent thermometer and single component white light emitter via synergy in energy transfer between ligands and Eu3.

The thermosensing and thermochromic behavior of one of our recently reported terpyridyl-imidazole based ternary europium tris-(ß-diketonate) complexes of the composition [Eu(tta)3(tpy-HImzphen)] (tta = 2-thenoyltrifluoroacetone and tpy-HImzphen = 2-(4-[2,2':6',2''] terpyridin-4'-yl-phenyl)-1H-phenanthro[9,10-d]imidazole) has been thoroughly investigated in this work. The said Eu(III) complex exhibits magnificent thermosensing as well as thermochromic properties and can be recommended as an excellent temperature sensor in a wide temperature domain of 273-343 K in terms of both emission intensity ratio (Sm = 5.78% K-1 at Tm = 343 K, δT = 0.012 K) and lifetime values (Sm = 3.36% K-1 at Tm = 333 K, δT = 0.009 K) or even in terms of its emitting color (red at 268 K, violet at 303 K, and blue at 343 K). Additionally, it displays remarkable solvent-induced luminescence behavior by displaying various emitting colors instead of its sole characteristic red emission upon varying the nature of the solvent. Finally, amalgamating these two features, we are able to attain white light emission (Commission Internationale de l'Eclairage coordinates: x = 0.34, y = 0.38) at 283 K from a single component. A plausible energy transfer mechanism has also been proposed in light of the existence of the ligand-to-metal charge transfer (LMCT) state as the quencher.

Morpholine, a strong contender for Fmoc removal in solid-phase peptide synthesis.

Morpholine, which scores 7.5 in terms of greenness and is not a regulated substance, could be considered a strong contender for Fmoc removal in solid-phase peptide synthesis (SPPS). Morpholine in dimethylformamide (DMF) (50%-60%) efficiently removes Fmoc in SPPS, minimizes the formation of diketopiperazine, and almost avoids the aspartimide formation. As a proof of concept, somatostatin has been synthesized using 50% morpholine in DMF with the same purity as when using 20% piperidine-DMF.

Controlling smoking: A smoking epidemic model with different smoking degrees in deterministic and stochastic environments.

Engaging in smoking not only leads to substantial health risks but also imposes considerable financial burdens. To deepen our understanding of the mechanisms behind smoking transmission and to address the tobacco epidemic, we examined a five-dimensional smoking epidemic model that accounts for different degrees of smoking under both deterministic and stochastic conditions. In the deterministic case, we determine the basic reproduction number, analyze the stability of equilibria with and without smoking, and investigate the existence of saddle-node bifurcation. Our analysis reveals that the basic reproduction number cannot completely determine the existence of smoking, and the model possesses bistability, indicating its dynamic is susceptible to interference from environmental noises. In the stochastic case, we establish sufficient conditions for the ergodic stationary distribution and the elimination of smokers by constructing appropriate Lyapunov functions. Numerical simulations suggest that the effects of inevitable random fluctuations in the natural environment on controlling the smoking epidemic may be beneficial, harmful, or negligible, which are closely related to the noise intensities, initial smoking population sizes, and the effective exposure rate of smoking transmission (ß). Given the uncontrollable nature of environmental random effects, effective smoking control strategies can be achieved by: (1) accurate monitoring of initial smoking population sizes, and (2) implementing effective measures to reduce ß. Therefore, it is both effective and feasible to implement a complete set of strong MPOWER measures to control smoking prevalence.

RadDiscord's Big Bang: Perspectives and Impact of Creation of a Successful Radiology Education Community.

The COVID-19 pandemic brought unprecedented challenges in radiology education. RadDiscord, a digital, open-access radiology educational platform now with over 4100 members internationally, emerged as a COVID-era innovation that has transformed radiology education, broken down institutional silos, and equalized access to high-quality education. This special report will discuss the origin of RadDiscord, overcoming early barriers, building an organization and community, innovation and impact, and the future of radiological education. This may offer helpful perspectives to trainees and educators who are interested in innovating in the realm of radiology education.

Synthesis, characterization, luminescence properties and deciphering the role of a terpyridyl-imidazole based ligand in the dissimilar luminescence sensitization of ternary lanthanide(III) tris-(ß-diketonate) complexes.

We designed four ternary lanthanide tris-(ß-diketonate) complexes of the form [Ln(tta)3(tpy-HImzphen)], where Ln = LaIII, EuIII, SmIII and TbIII; tta = (2-theonyltrifluoroacetonate) and tpy-HImzphen = 2-(4-[2,2':6',2'']terpyridin-4'-yl-phenyl)-1H-phenanthro[9,10-d]imidazole. All the complexes have been thoroughly characterized by standard analytical tools and spectroscopic techniques including single crystal X-ray diffraction. In situ generation of the complexes was also monitored via absorption and emission spectroscopy upon incremental addition of the respective lanthanide precursor {Ln(tta)3(H2O)2} to the dichloromethane solution of the terpyridyl-imidazole ligand. The photophysical behaviors of all the complexes were thoroughly investigated via absorption and both steady-state and time-resolved emission spectroscopic techniques. The emission spectral measurements were carried out at both room temperature and 77 K to understand the deactivation dynamics of the excited states and elucidate the distinctive luminescence responses from the four lanthanide metal ions owing to the introduction of the terpyridyl-based ancillary ligand.

Circulating renin-angiotensin systems mediated feedback controls over the mean-arterial pressure.

The renin-angiotensin systems play pivotal role in cardiovascular physiology through its effects on regulating blood pressure and electrolyte homeostasis. Components of circulating RAS (cRAS) that include precursor angiotensinogen, two critical enzymes (renin and angiotensin-converting enzyme, ACE), their bioactive products, angiotensin- I, II together with its receptors (AT1R and AT2R) essentially determine this homeostasis. Most classical studies, however, showed the deleterious role of cRAS in elevating the blood pressure. Contemporary discovery of non-canonical components of the RAS has challenged this classic hypothesis that it can only exert deleterious effects on the cardiovascular systems. Using the classic cRAS model, we have designed in-silico experiments to test the hypothesis that AT2R-mediated feedback effects play pivotal role for maintaining the normal variation of the mean-arterial pressure (MAP).Beside the AT2R-mediation of downstream singling pathways consisting of several non-canonical RAS components, this study first time illustrated AT2R mediated feedback controls over the blood pressure regulation: one that impedes AT1R activity, and the other that downregulates renin. It has been shown that relatively stronger suppression of renin activity significantly contributes in maintaining the normal MAP and that tight AT2R-mediated regulation is relaxed in hyper-and hypotension. This control mechanism is noted to be robustly maintained with the MAP variations through an established linear steady-state relationship among renin, angiotensin I and angiotensin II. This examination suggests that AT2R-mediated downregulation of renin activities potentially counteracts the AT1R-mediated deleterious actions of Ang II. This study, therefore, provides a solid ground for considering different AT2 receptor adaptor protein and direct agonism at AT2R that can cause greater effects along with contemporary approaches of blocking AT1R mediation to attenuate hypertension or other cardiovascular disorders.

Changes in the associations between malaria incidence and climatic factors across malaria endemic countries in Africa and Asia-Pacific region.

Empirical evidence supporting the associations between malaria incidence and climatic factors has remained controversial, buffering the progress in the Global Malaria Program that aims to eliminate 90% of the world malaria burden by 2030. This study has aimed to evaluate the nature and extent at which these relations are maintained across all the malaria endemic countries of Africa and Asia-Pacific region. We have utilized the last two decades of malaria incidence, annual minimum temperature, and annual precipitation time series data (2000-2020) for the two most malaria-impacted regions. These data were fitted in the generalized linear model and the mixed effects model. The results showed that there exists a large heterogeneity in malaria incidence across the countries, and between the regions. Last two decadal tendencies showed significant reductions in the disease burden in almost all the countries in the Asia Pacific, with several exceptions or relatively slowed reductions in the Africa. We found significant changes in the positive linear associations between malaria incidence, annual minimum temperature, and annual precipitation across African countries. Many Asia-Pacific countries namely Bangladesh, Bhutan, Indonesia, South Korea, Nepal, Thailand, Vietnam showed negative effects in the associations with the annual precipitation. This study indicates that increasing temperature within the range of 12-30 °C can generate positive effects on malaria incidence, but the nature and extent of precipitation effects vary across countries and at a large regional scale.

PET/MR of pediatric bone tumors: what the radiologist needs to know.

Integrated 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/magnetic resonance (MR) imaging can provide "one stop" local tumor and whole-body staging in one session, thereby streamlining imaging evaluations and avoiding duplicate anesthesia in young children. 18F-FDG PET/MR scans have the benefit of lower radiation, superior soft tissue contrast, and increased patient convenience compared to 18F-FDG PET/computerized tomography scans. This article reviews the 18F-FDG PET/MR imaging technique, reporting requirements, and imaging characteristics of the most common pediatric bone tumors, including osteosarcoma, Ewing sarcoma, primary bone lymphoma, bone and bone marrow metastases, and Langerhans cell histiocytosis.

Ecological risk assessment of organochlorine pesticide mixture in South China Sea and East China Sea under the effects of seasonal changes and phase-partitioning.

Organochlorine pesticides (OCPs), chlorinated hydrocarbon derivatives extensively used in agriculture and chemical industry, have been banned for several decades in most developed countries. However, OCPs act as persistent organic pollutants due to their semi-volatility nature, high ability for wide range transportation and faster bioaccumulation, and thus it has remained as a topical global concern. This study focuses on OCP distributions, sources and associated ecological risks in the globally important OCP source-sink regions of South China Sea (SCS) and East China Sea (ECS). Given the co-exposure of multiple OCPs that undermine the classical risk assessment of single OCP species, a two-tier mixture risk assessment approach has been employed with explicit consideration of seasonal changes and phase-partitioning effects. The results indicate existence of multiple sources varied across the seasons and between the dissolved and particulate phases. Potential sources include the current-use of lindane or historical use of technical HCH, input of technical DDTs, long-range atmospheric transport, and deposition of HCB from land surfaces. There are no wide high-risk zones. Dissolved HCB and DDTs have posed low-to-medium levels of risks broadly distributed across the seasons. Relatively greater risks are observed in summer in the both dissolved and particulate phases. The study has shown the importance of considering mixture risk assessments with the effects of phase-partitioning and seasonal changes for efficient oceanic risk management.

Exchange-driven slow relaxation of magnetization in NiII2LnIII2 (LnIII = Y, Gd, Tb and Dy) butterfly complexes: experimental and theoretical studies.

The tetranuclear NiII2LnIII2 complexes, [{L'2{Ni(MeOH)(µ-OAc)}2(µ3-MeO)2Ln2}, LnIII = YIII (1), GdIII (2), TbIII (3), and DyIII (4)], were prepared using a Schiff base ligand, H3L [H3L = 3-{(2-hydroxy-3-methoxybenzylidene)amino}-2-(2-hydroxy-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one, where {L'}3- is the deprotonated open structure of H3L]. X-ray crystallographic analysis of 1-4 revealed that all the complexes crystallized in the orthorhombic (Pbcn) space group, and possessed an isostructural tetranuclear butterfly or defect dicubane like core. Direct current magnetic susceptibility measurements performed on 2-4 revealed that all these complexes show an intramolecular ferromagnetic exchange coupling. Well resolved zero-field out-of-phase signals in ac magnetic susceptibility measurements were observed only in the case of 3 (Ueff = 13.4 K; τ0 = 4.1(7) × 10-7 s). This was attributed to the comparatively strong NiII-TbIII magnetic exchange coupling. DFT and ab initio calculations were carried out on 1-4 to ascertain the nature of the ferromagnetic NiII-LnIII (JNi-Ln) and LnIII-LnIII (JLn-Ln) interactions. Magnetic anisotropy and magnetic relaxation mechanisms were discussed in detail for 3 and 4. Theoretical studies provide a rationale for the slow relaxation of magnetization in 3.

Solid-Phase Synthesis of an "Inaccessible" hGH-Derived Peptide Using a Pseudoproline Monomer and SIT-Protection for Cysteine.

The solid-phase peptide synthesis (SPPS) of the C-terminal sequence of hGH with one extra Tyr attached to its N-terminus (total of 16 residues with a disulfide bridge) has been accomplished for the first time by optimizing several synthetic parameters. First of all, the two Ser residues (positions 9 and 13 of the molecule) have been introduced as a single amino acid, Fmoc-Ser(ψMe,Mepro)-OH, demonstrating that the acylation of these hindered moieties is possible. This allows us to avoid the use of the corresponding dipeptides, Fmoc-AA-Ser(ψMe,Mepro)-OH, which are very often not commercially available or very costly. The second part of the sequence has been elongated via a double coupling approach using two of the most effective coupling methods (DIC-OxymaPure and HATU-DIEA). Finally, the disulfide bridging has been carried out very smoothly by a chemoselective thiol-disulfide interchange reaction between a SIT (sec-isoamyl mercaptan)-protected Cys residue and the free thiol of the second Cys. The synthesis of this short peptide has evidenced that SPPS is a multifactorial process which should be optimized in each case.

Phase partitioning effects on seasonal compositions and distributions of terrigenous polycyclic aromatic hydrocarbons along the South China Sea and East China Sea.

Polycyclic aromatic hydrocarbons (PAHs) have posed serious risk to marine ecosystems due to their carcinogenic properties, and persistence in the environment and elevated bioaccumulation. It, therefore, becomes essential to examine spatial distribution, composition, and sources of PAHs. In this study, we have examined these PAH variations in the South China Sea (SCS) and East China Sea (ECS), that are experiencing rapid population and economic growth by the surrounding developing countries. It revealed high seasonal variations that significantly differ between dissolved and particulate PAHs concentrations. Spatial variations of PAHs across sites remain relatively insignificant. Persistently high particulate concentrations of the Naphthalene (Nap) were observed, whereas the dissolved concentrations of Fluorene (Flu) and Phenanthrene (Phen) remained prevalent across all the seasons. The result of non-metric multidimensional scaling (NMDS) strongly reflects the weak dispersions of PAHs across the seasons and the contrasting effects of the phase partitioning. Principal component analysis indicates that the primary source of PAH contamination is coal tar or petroleum distillation. However, estimated risk quotient (RQ) values of both the dissolved and particulate PAHs in all the seasons are far below the high-risk levels, while dissolved PAHs displayed relatively higher values. This study signifies the importance of phase petitioning for PAHs monitoring and potential risk assessments.

Fracture through tracking pin sites following a robotic-assisted total knee arthroplasty.

The use of computer-navigated, robotic-assisted total knee arthroplasty (TKA) is expanding as the result of widespread efforts to improve the precision of implant placement and to restore mechanical, anatomic, and kinematic alignment. The procedure requires placement of femoral and tibial pins to mount the robotic tracking system. Fractures through tracking pin sites following robotic-assisted TKA are rare; only 30 cases have been reported to our knowledge. It is probable that this complication will become more frequent as the use of robotic-assisted TKAs continues to grow. We report the case of a 67-year-old female who suffered a fracture of the femur through two pin sites 3 months after a robotic-assisted TKA. We believe that this report is the first case in the radiologic literature. Our case demonstrates some of the difficulties of recognizing this complication and raises questions about appropriate post-operative imaging.

Site Density Functional Theory and Structural Bioinformatics Analysis of the SARS-CoV Spike Protein and hACE2 Complex.

The entry of the SARS-CoV-2, a causative agent of COVID-19, into human host cells is mediated by the SARS-CoV-2 spike (S) glycoprotein, which critically depends on the formation of complexes involving the spike protein receptor-binding domain (RBD) and the human cellular membrane receptor angiotensin-converting enzyme 2 (hACE2). Using classical site density functional theory (SDFT) and structural bioinformatics methods, we investigate binding and conformational properties of these complexes and study the overlooked role of water-mediated interactions. Analysis of the three-dimensional reference interaction site model (3DRISM) of SDFT indicates that water mediated interactions in the form of additional water bridges strongly increases the binding between SARS-CoV-2 spike protein and hACE2 compared to SARS-CoV-1-hACE2 complex. By analyzing structures of SARS-CoV-2 and SARS-CoV-1, we find that the homotrimer SARS-CoV-2 S receptor-binding domain (RBD) has expanded in size, indicating large conformational change relative to SARS-CoV-1 S protein. Protomer with the up-conformational form of RBD, which binds with hACE2, exhibits stronger intermolecular interactions at the RBD-ACE2 interface, with differential distributions and the inclusion of specific H-bonds in the CoV-2 complex. Further interface analysis has shown that interfacial water promotes and stabilizes the formation of CoV-2/hACE2 complex. This interaction causes a significant structural rigidification of the spike protein, favoring proteolytic processing of the S protein for the fusion of the viral and cellular membrane. Moreover, conformational dynamics simulations of RBD motions in SARS-CoV-2 and SARS-CoV-1 point to the role in modification of the RBD dynamics and their impact on infectivity.

Substituent effect of benzyl moiety in nitroquinoxaline small molecules upon DNA binding: Cumulative destacking of DNA nucleobases leading to histone eviction.

Cooperative disruption of Watson-Crick hydrogen bonds, as well as base-destacking, is shown to be triggered by a quinoxaline-based small molecule consisting of an N,N-dimethylaminopropyl tether, and a para-substituted benzyl moiety. This events lead to superstructure formation and DNA condensation as evident from biophysical experiments and classical molecular dynamics simulations. The DNA superstructure formation by mono-quinoxaline derivatives is highly entropically favored and predominantly driven by hydrophobic interactions. Furthermore, oversupercoiling of DNA and base-destacking cumulatively induces histone eviction from in-vitro assembled nucleosomes at lower micromolar concentrations implicating biological relevance. The DNA structural modulation and histone eviction capacity of the benzyl para-substituents are in the order: -I > -CF3> -Br > -Me > -OMe > -OH, which is largely guided by the polarity of benzyl para-substituent and the resulting molecular topology. The most hydrophobic derivative 3c with para-iodo benzyl moiety causes maximal disruption of base pairing and generation of superstructures. Both these events gradually diminish as the polarity of the benzyl para-substituent increases. On the other hand, quinoxaline derivatives having heterocyclic ring instead of benzyl ring, or in the absence of N,N-dimethylamino head-group, is incapable of inducing any DNA structural change and histone eviction. Further, the quinoxaline compounds displayed potent anticancer activities against different cancer cell lines which directly correlates with the hydrophobic effects of the benzyl para-substituents. Overall, the present study provides new insights into the mechanistic approach of DNA structural modulation driven histone eviction guided by the hydrophobicity of synthesized compounds leading to cellular cytotoxicity towards cancer cells.

Chemoselective Disulfide Formation by Thiol-Disulfide Interchange in SIT-Protected Cysteinyl Peptides.

Chemoselective disulfide formation is accomplished through a thiol-disulfide interchange approach using sec-isoamyl mercaptan (SIT) as an alkyl sulfenyl-protecting group of one of the Cys residues involved in the pairing. SIT has a dual and unique characteristic, acting as a masking group during the synthesis and directing disulfide formation in the presence of a free thiol. This novel approach is illustrated by the synthesis of several peptides of biological interest.

Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants.

The emergence of a variety of highly transmissible SARS-CoV-2 variants, the causative agent of COVID-19, with multiple spike mutations poses serious challenges in overcoming the ongoing deadly pandemic. It is, therefore, essential to understand how these variants gain enhanced ability to evade immune responses with a higher rate of spreading infection. To address this question, here we have individually assessed the effects of SARS-CoV-2 variant-specific spike (S) protein receptor-binding domain (RBD) mutations E484K, K417N, L452Q, L452R, N501Y, and T478K that characterize and differentiate several emerging variants. Despite the hundreds of apparently neutral mutations observed in the domains other than the RBD, we have shown that each RBD mutation site is differentially engaged in an interdomain allosteric network involving mutation sites from a distant domain, affecting interactions with the human receptor angiotensin-converting enzyme-2 (ACE2). This allosteric network couples the residues of the N-terminal domain (NTD) and the RBD, which are modulated by the RBD-specific mutations and are capable of propagating mutation-induced perturbations between these domains through a combination of structural changes and effector-dependent modulations of dynamics. One key feature of this network is the inclusion of compensatory mutations segregated into three characteristically different clusters, where each cluster residue site is allosterically coupled with specific RBD mutation sites. Notably, each RBD mutation acted like a positive allosteric modulator; nevertheless, K417N was shown to have the largest effects among all of the mutations on the allostery and thereby holds the highest binding affinity with ACE2. This result will be useful for designing the targeted control measure and therapeutic efforts aiming at allosteric modulators.

A Carbohydrate-based Synthetic Approach to Diverse Structurally and Stereochemically Complex Chiral Polyheterocycles.

Chiral polyheterocycles are one of the most frequently encountered scaffolds in natural products and in current drugs repertoire. A carbohydrate-based diversity oriented synthetic (DOS) approach has been employed for gaining access to many structurally diverse and stereochemically complex rigid polyheterocyclic molecules with multiple chiral hydroxyl groups to enhance aqueous solubility. Inexpensive chiral pool of D-Glucose has been judiciously exploited to get access of complex chiral polyheterocyclic structures using inexpensive, common achiral reagents and domino-Knoevenagel hetero-Diels-Alder (DKHDA) reaction as one of the key synthetic tools. Stereochemistry of newly generated stereocenters of polycyclic structures are unambiguously determined through NMR and X-ray crystallographic study. A chemoinformatic comparison (PCA and PMI) with 40 branded blockbuster drugs showed that newly generated polyheterocycles have good three-dimensional scaffold diversity and most of these pass the Lipinski filter of drug-likeness.