Searching for "Greener" Bioequivalents of CF3 to Lower its Environmental Impact.

Considering the broad use of the trifluoromethyl functional group (-CF3) in medicinal chemistry and taking into account the recent concerns on the negative environmental effects of CF3 containing compounds, we are searching for "greener" alternatives. Thus, different chemical groups (i.e. iodide, fluoride, cyclopropyl, isopropyl, cyclobutyl, 3-oxetyl, 2-oxetyl, methylsulfide, pentafluorosulfide, methylsulfonyl and sulfonamide) have been considered as potential bioequivalents of -CF3 aiming to use them in compounds with therapeutic interest instead of the polyfluoride functionality. Different structural (molecular surface and volume) and physicochemical (electronic and lipophilic) aspects of the bioequivalent functionalities proposed have been theoretically calculated and compared to those of -CF3. Additionally, the corresponding phenyl derivatives carrying these functionalities have been purchased or prepared and their experimental lipophilicity (i.e. LogP) measured using shake-flask experiments and UV-vis spectroscopy.

A Tale of Two Proteases: MPro and TMPRSS2 as Targets for COVID-19 Therapies.

Considering the importance of the 2019 outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in the coronavirus disease 2019 (COVID-19) pandemic, an overview of two proteases that play an important role in the infection by SARS-CoV-2, the main protease of SARS-CoV-2 (MPro) and the host transmembrane protease serine 2 (TMPRSS2), is presented in this review. After summarising the viral replication cycle to identify the relevance of these proteases, the therapeutic agents already approved are presented. Then, this review discusses some of the most recently reported inhibitors first for the viral MPro and next for the host TMPRSS2 explaining the mechanism of action of each protease. Afterward, some computational approaches to design novel MPro and TMPRSS2 inhibitors are presented, also describing the corresponding crystallographic structures reported so far. Finally, a brief discussion on a few reports found some dual-action inhibitors for both proteases is given. This review provides an overview of two proteases of different origins (viral and human host) that have become important targets for the development of antiviral agents to treat COVID-19.

Green synthesis of nitroaryl thioureas: Towards an improved preparation of guanidinium DNA binders.

We present a general efficient green method for the preparation of nitro N,N'-diaryl thioureas via a one-pot method using cyrene as a solvent with almost quantitative yields. This confirmed the viability of cyrene as a green alternative to THF in the synthesis of thiourea derivatives. After screening different reducing conditions, the nitro N,N'-diaryl thioureas were selectively reduced using Zn dust in the presence of water and acid to the corresponding amino N,N'-diaryl thioureas. These were then used to test the installation of the Boc-protected guanidine group with N,N'-bis-Boc protected pyrazole-1-carboxamidine as a guanidylating reagent not requiring mercury(II) activation. Finally, the TFA salts obtained after Boc-deprotection of two sample compounds were tested for their affinity towards DNA showing no binding.

New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds.

Antimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bacterial bet-hedging strategy, will lead to new molecular entities displaying low selective pressure, thereby reducing the insurgence of AMR. Here, we describe a way to target (p)ppGpp (guanosine tetra- or penta-phosphate) signaling, a non-essential pathway involved in the formation of persisters, with a structure-based approach. A superfamily of enzymes called RSH (RelA/SpoT Homolog) regulates the intracellular levels of this alarmone. We virtually screened several fragment libraries against the (p)ppGpp synthetase domain of our RSH chosen model RelSeq, selected three main chemotypes, and measured their interaction with RelSeq by thermal shift assay and STD-NMR. Most of the tested fragments are selective for the synthetase domain, allowing us to select the aminobenzoic acid scaffold as a hit for lead development.

Chiral 2-phenyl-3-hydroxypropyl esters as PKC-alpha modulators: HPLC enantioseparation, NMR absolute configuration assignment, and molecular docking studies.

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. In our previous work, we identified in racemate 1-2, based on the 2-benzyl-3-hydroxypropyl ester scaffold, two new potent and promising PKCα and PKCδ ligands, targeting the C1 domain of these two kinases. Herein, we report the resolution of the racemates by enantioselective semi-preparative HPLC. The attribution of the absolute configuration (AC) of homochirals 1 was performed by NMR, via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (MTPA or Mosher's acid). Moreover, the match between the experimental and predicted electronic circular dichroism (ECD) spectra confirmed the assigned AC. These results proved that Mosher's esters can be properly exploited for the determination of the AC also for chiral primary alcohols. Lastly, homochiral 1 and 2 were assessed for binding affinity and functional activity against PKCα. No significative differences in the Ki of the enantiopure compounds was observed, thus suggesting that chirality does not seem to play a significant role in targeting PKC C1 domain. These results are in accordance with the molecular docking studies performed using a new homology model for the human PKCαC1B domain.

Optimised Synthesis of the Bacterial Magic Spot (p)ppGpp Chemosensor PyDPA.

Guanosine penta- or tetraphosphate (pppGpp or ppGpp, respectively) is a nucleotide signalling molecule with a marked effect on bacterial physiology during stress. Its accumulation slows down cell metabolism and replication, supposedly leading to the formation of the antibiotic-tolerant persister phenotype. A specifically tailored fluorescent chemosensor, PyDPA, allows the detection of (p)ppGpp in solution with high selectivity, relative to that of other nucleotides. Herein, an optimised synthetic approach is presented that improves the overall yield from 9 to 67 % over 7 steps. The simplicity and robustness of this approach will allow groups investigating the many facets of (p)ppGpp easy access to this probe.