Organo-catalysis as emerging tools in organic synthesis: aldol and Michael reactions

Organocatalysis has occupied sustainable position in organic synthesis as a powerful tool for the synthesis of enantiomeric-rich compounds with multiple stereogenic centers. Among the various organic molecules for organocatalysis, the formation of carbon–carbon is viewed as a challenging issue in organic synthesis. The asymmetric aldol and Michael addition reactions are the most significant methods for C–C bond forming reactions. These protocols deliver a valuable path to access chiral molecules, which are useful synthetic hybrids in biologically potent candidates and desirable versatile pharmaceutical intermediates. This work highlighted the impact of organocatalytic aldol and Michael addition reactions in abundant solvent media. It focused on the crucial methods to construct valuable molecules with high enantio- and diastereo-selectivity.

Power and Weakness of Repetition – Evaluating the Phylogenetic Signal From Repeatomes in the Family Rosaceae With Two Case Studies From Genera Prone to Polyploidy and Hybridization (Rosa and Fragaria)

Plant genomes consist, to a considerable extent, of non-coding repetitive DNA. Several studies showed that phylogenetic signals can be extracted from such repeatome data by using among-species dissimilarities from the RepeatExplorer2 pipeline as distance measures. Here, we advanced this approach by adjusting the read input for comparative clustering indirectly proportional to genome size and by summarizing all clusters into a main distance matrix subjected to Neighbor Joining algorithms and Principal Coordinate Analyses. Thus, our multivariate statistical method works as a “repeatomic fingerprint,” and we proved its power and limitations by exemplarily applying it to the family Rosaceae at intrafamilial and, in the genera Fragaria and Rosa, at the intrageneric level. Since both taxa are prone to hybridization events, we wanted to show whether repeatome data are suitable to unravel the origin of natural and synthetic hybrids. In addition, we compared the results based on complete repeatomes with those from ribosomal DNA clusters only, because they represent one of the most widely used barcoding markers. Our results demonstrated that repeatome data contained a clear phylogenetic signal supporting the current subfamilial classification within Rosaceae. Accordingly, the well-accepted major evolutionary lineages within Fragaria were distinguished, and hybrids showed intermediate positions between parental species in data sets retrieved from both complete repeatomes and rDNA clusters. Within the taxonomically more complicated and particularly frequently hybridizing genus Rosa, we detected rather weak phylogenetic signals but surprisingly found a geographic pattern at a population scale. In sum, our method revealed promising results at larger taxonomic scales as well as within taxa with manageable levels of reticulation, but success remained rather taxon specific. Since repeatomes can be technically easy and comparably inexpensively retrieved even from samples of rather poor DNA quality, our phylogenomic method serves as a valuable alternative when high-quality genomes are unavailable, for example, in the case of old museum specimens.

Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2

Background The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19. Results Molecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target. Conclusions Hybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.

Gradual evolution of allopolyploidy in Arabidopsis suecica

Most diploid organisms have polyploid ancestors. The evolutionary process of polyploidization is poorly understood but has frequently been conjectured to involve some form of ‘genome shock’, such as genome reorganization and subgenome expression dominance. Here we study polyploidization in Arabidopsis suecica, a post-glacial allopolyploid species formed via hybridization of Arabidopsis thaliana and Arabidopsis arenosa. We generated a chromosome-level genome assembly of A. suecica and complemented it with polymorphism and transcriptome data from all species. Despite a divergence around 6 million years ago (Ma) between the ancestral species and differences in their genome composition, we see no evidence of a genome shock: the A. suecica genome is colinear with the ancestral genomes; there is no subgenome dominance in expression; and transposon dynamics appear stable. However, we find changes suggesting gradual adaptation to polyploidy. In particular, the A. thaliana subgenome shows upregulation of meiosis-related genes, possibly to prevent aneuploidy and undesirable homeologous exchanges that are observed in synthetic A. suecica, and the A. arenosa subgenome shows upregulation of cyto-nuclear processes, possibly in response to the new cytoplasmic environment of A. suecica, with plastids maternally inherited from A. thaliana. These changes are not seen in synthetic hybrids, and thus are likely to represent subsequent evolution.

Antimicrobial Activity of Quinoline-Based Hydroxyimidazolium Hybrids

Eight quinoline-based hydroxyimidazolium hybrids 7a–h were prepared and evaluated in vitro against a panel of clinically important fungal and bacterial pathogens, including mycobacteria. Hybrid compounds 7c–d showed remarkable antifungal activity against Cryptococcus neoformans with a minimum inhibitory concentration (MIC) value of 15.6 µg/mL. Against other opportunistic fungi such as Candida spp. and Aspergillus spp., these hybrids showed MIC values of 62.5 µg/mL. Regarding their antibacterial activity, all the synthetic hybrids demonstrated little inhibition of Gram-negative bacteria (MIC ≥50 µg/mL), however, hybrid 7b displayed >50% inhibition against Klebsiella pneumoniae at 20 µg/mL and full inhibition at 50 µg/mL. Moreover, this hybrid was shown to be a potent anti-staphylococcal molecule, with a MIC value of 2 µg/mL (5 µM). In addition, hybrid 7h also demonstrated inhibition of Staphylococcus aureus at 20 µg/mL (47 µM). Hybrids 7a and 7b were the most potent against Mycobacterium tuberculosis H37Rv with MIC values of 20 and 10 µg/mL (46 and 24 µM), respectively. The 7b hybrid demonstrated high selectivity in killing S. aureus and M. tuberculosis H37Rv in comparison with mammalian cells (SI >20), and thus it can be considered a hit molecule for mechanism of action studies and the exploration of related chemical space.

Paternal Contribution to Banana (Musa sapientum L.) & Plantain (Musa paradisiaca L.) Progenies & Progeny Ploidy Composition in a Polycross Mating System Using RAPD & Flow Cytometry

Aims: A 4x – 2x polycross mating design of 4 tetraploid female parents was established to determine paternal contributions of 3 diploid male parents to resulting progenies, their ploidy composition and genetic diversity of synthetic hybrids. Study Design: The polycross mating design comprised 2 blocks having both maternal and paternal selections, with seed parents replicated at 12 plants per clone. Each crossing block had 31 plants of each of the three male parents. Place and Duration of Study: International Institute of Tropical Agriculture (IITA) High Rainfall Station, Onne (4º51’N, 7º03’E, 10 m above sea level), Rivers State, South-South Nigeria for a period of 24 months. Methodology: At maturity of maternal parents (TMPx 2796-5; TMPx 1658-4; TMPx 5511-2; and TMPx 7152-2), fruit bunches were harvested, ripened and the seeds extracted. Hard seeds obtained were germinated in vivo in seed trays and emerging seedlings transplanted to perforated nursery bags. At 12 weeks, DNA was extracted from candle leaf for RAPD analysis of 80 progenies and the 3 pollen parents. Ploidy status of progenies was determined using flow cytometry method. Results: There was significant unequal paternal contribution to Musa polycross progenies with 3 maternal parents; TMPx 2796-5, TMPx 5511-2, and TMPx 1658-4. Two of the 3 paternal parents had progenies with all 4 maternal parents while TMB2x 5105-1 did not have any progeny with TMPx 2796-5. Progenies exhibited 4 ploidy levels with frequency differing with each female parent: TMPx 7152-2 produced 100% 3x progeny; TMPx 5511-2, 63% 3x and 37% 2x; TMPx 2796-5, 91% 3x and 9% 2x and TMPx 1658-4, 82% 3x, 9% 2x, 6% 4x and 3% 5x. The 5x progeny was recorded in the first ratoon crop. The second ratoon crop had only triploids. Conclusion: The high frequency of 3x progenies from all maternal types in this study, suggests the effectiveness of the polycross mating design in Musa improvement.

Synthesis, Antibacterial Activities, Mode of Action and Acute Toxicity Studies of New Oxazolidinone-Fluoroquinolone Hybrids

To combat bacterial resistance, a series of new oxazolidinone-fluoroquinolone hybrids have been synthesized and characterized. All synthetic hybrids were preliminarily evaluated for their in vitro antibacterial activities against 6 standard strains and 3 clinical isolates. The majority of hybrids displayed excellent activities against Gram-positive bacteria, but limited activities against Gram-negative bacteria. Hybrids OBP-4 and OBP-5 were found to be the most promising compounds. Further, in vitro antibacterial activities, mode of action and acute toxicity in mice of hybrids OBP-4 and OBP-5 were investigated. Hybrids OBP-4 and OBP-5 exhibited potent activities against Gram-positive bacteria, including drug-resistant strains. Correspondingly, studies on the mode of action of hybrids OBP-4 and OBP-5 indicated a strong inhibitory activity on protein synthesis by binding the active site of 50S subunit, but a weak inhibitory action on DNA synthesis. In addition, LD50 values of hybrids OBP-4 and OBP-5 in the acute oral toxicity were larger than 2000 mg/kg, suggesting a good safety profile.

Synthetic hybrids of six yeast species

Allopolyploidy generates diversity by increasing the number of copies and sources of chromosomes. Many of the best-known evolutionary radiations, crops, and industrial organisms are ancient or recent allopolyploids. Allopolyploidy promotes differentiation and facilitates adaptation to new environments, but the tools to test its limits are lacking. Here we develop an iterative method to combine the genomes of multiple budding yeast species, generating Saccharomyces allopolyploids of an unprecedented scale. Chromosomal instability and cell size increased dramatically as additional copies of the genome were added, but we were able to construct synthetic hybrids of up to six species. The six-species hybrids initially grew slowly, but they rapidly adapted when selection to a novel environment was applied, even as they retained traits from multiple species. These new synthetic yeast hybrids have potential applications for the study of polyploidy, genome stability, chromosome segregation, cancer, and bioenergy.One sentence summaryWe constructed six-species synthetic hybrids and showed that they were chromosomally unstable but able to adapt rapidly.