The Pharmaceutical Industry in 2020. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

Although the pharmaceutical industry will remember 2020 as the year of COVID-19, it is important to highlight that this year has been the second-best-together with 1996-in terms of the number of drugs accepted by the US Food and Drug Administration (FDA). Each of these two years witnessed the authorization of 53 drugs-a number surpassed only in 2018 with 59 pharmaceutical agents. The 53 approvals in 2020 are divided between 40 new chemical entities and 13 biologic drugs (biologics). Of note, ten monoclonal antibodies, two antibody-drug conjugates, three peptides, and two oligonucleotides have been approved in 2020. Close inspection of the so-called small molecules reveals the significant presence of fluorine atoms and/or nitrogen aromatic heterocycles. This report analyzes the 53 new drugs of the 2020 harvest from a strictly chemical perspective, as it did for those authorized in the previous four years. On the basis of chemical structure alone, the drugs that received approval in 2020 are classified as the following: biologics (antibodies, antibody-drug conjugates, and proteins); TIDES (peptide and oligonucleotides); natural products; fluorine-containing molecules; nitrogen aromatic heterocycles; and other small molecules.

Design and synthesis of mono-and di-pyrazolyl-s-triazine derivatives, their anticancer profile in human cancer cell lines, and in vivo toxicity in zebrafish embryos.

s-Triazine is considered a privileged structure, as it is found in several FDA-approved drugs. In the framework of our ongoing medicinal chemistry project based on the use of s-triazine as a scaffold, we synthesized a series of mono- and di-pyrazolyl-s-triazine derivatives and tested them against four human cancer cell lines, namely Human breast carcinoma (MCF 7 and MDA-MB-231), hepatocellular carcinoma (HepG2), colorectal carcinoma (LoVo), and leukemia (K562). The cell viability assay revealed that most of the s-triazine compounds induced cytotoxicity in all four types of human cancer cell lines, however, compounds 4a, and 6g, both of them have a piperidine moiety in their structure were most effective. These two compounds affected the cell viability of cancer cells, with IC50 values within the range between 5 to 9 µM. The cell cycle analysis showed that 4a and 6g induced S and G2/M phase cell cycle arrest in K562 cells. This could be the mechanism by which these molecules induced cytotoxicity in tested cancer cells. The prepared compounds were tested in zebrafish embryos to evaluate in vivo and developmental toxicity of the pyrazolyl-s-triazine derivatives in animals. None of the derivatives were lethal in the concentration range tested.

Crystal structure, spectroscopic studies and theoretical studies of thiobarbituric acid derivatives: understanding the hydrogen-bonding patterns.

In addition to their wide-ranging applications in the pharmaceutical industry, thiobarbituric acid (TBA) derivatives are also known to possess applications in engineering and materials science. 20 TBA derivatives, with diversity at the N and C-5 positions through acylation, Schiff base formation, Knoevenagel condensation, thioamide and enamine formation, were studied. The absolute configurations for six derivatives, namely 5-acetyl-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C10H14N2O3S, A01, 1,3-diethyl-5-propionyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C11H16N2O3S, A02, tert-butyl [1-(1,3-diethyl-4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate, C18H29N3O5S, A06, 1,3-diethyl-4,6-dioxo-2-thioxo-N-(p-tolyl)hexahydropyrimidine-5-carbothioamide, C16H19N3O2S2, A13, 5-(1-aminoethylidene)-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C10H15N3O2S, A17, and 5-(1-aminopropylidene)-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C11H17N3O2S, A18, were confirmed by single-crystal X-ray crystallography, which indicates the formation of intramolecular hydrogen bonding in all six cases and intermolecular hydrogen bonding for A17. In A13, the presence of two intramolecular hydrogen bonds was observed. The stabilization of the enol form over the keto form was confirmed by computation. In order to convert the keto form to the enol form, an energy barrier of 55.05 kcal mol-1 needs to be overcome, as confirmed by transition-state calculations.

In Vitro Antibacterial Activity of Teixobactin Derivatives on Clinically Relevant Bacterial Isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) are included on the WHO high priority list of pathogens that require urgent intervention. Hence emphasis needs to be placed on developing novel class of molecules to tackle these pathogens. Teixobactin is a new class of antibiotic that has demonstrated antimicrobial activity against common bacteria. Here we examined the antimicrobial properties of three Teixobactin derivatives against clinically relevant bacterial isolates taken from South African patients. The minimum inhibitory concentration (MIC), the minimal bactericidal concentration (MBC), the effect of serum on MICs and the time-kill kinetics studies of our synthesized Teixobactin derivatives (3, 4, and 5) were ascertained following the CLSI 2017 guidelines and using the broth microdilution method. Haemolysis on red blood cells (RBCs) and cytotoxicity on peripheral blood mononuclear cells (PBMCs) were performed to determine the safety of these compounds. The MICs of 3, 4, and 5 against reference strains were 4-64 µg/ml, 2-64 µg/ml, and 0.5-64 µg/ml, respectively. The MICs observed for MRSA were (3) 32 µg/ml, (4) 2-4 µg/ml and (5) 2-4 µg/ml whilst those for VRE were (3) 8-16 µg/ml, (4) 4 µg/ml and (5) 2-16 µg/ml, respectively. In the presence of 50% human serum, there was no significant effect on the MICs. The compounds did not exhibit any effect on cell viability at their effective concentrations. Teixobactin derivatives (3, 4, and 5) inhibited bacterial growth in drug-resistant bacteria and hence emerge as potential antimicrobial agents. Molecular dynamic simulations suggested that the most dominant binding mode of Lys10-teixobactin (4) to lipid II is through the amide protons of the cycle, which is identical to data described in the literature for the natural teixobactin hence predicting the possibility of a similar mechanism of action.

Investigation of the N-Terminus Amino Function of Arg10-Teixobactin.

Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In this regard, a large number of analogs with substitutions in both the cycle and the tail has been described. Here, we report the contribution of the N-terminus residue, N-Me-d-Phe, to the activity of Arg10-teixobactin. On the basis of our findings, we conclude that the N-terminus accepts minimum changes but not the presence of long alkyl chains. The presence of a positive charge is a requirement for the activity of the peptide. Furthermore, acylation of the N-terminus leads to total loss of activity.

The Pharmaceutical Industry in 2016. An Analysis of FDA Drug Approvals from a Perspective of the Molecule Type.

This is an analysis from a chemical point of view of the 22 drugs accepted by the FDA during 2016. The different drugs from the 2016 "harvest" have been classified according to their chemical structure: antibodies; TIDES (oligonucleotides and peptides); amino acids and natural products; drug combination; and small molecules.