Degraders (e.g. PROTACs, SNIPERs, degronimers etc.) are a new modality offering increasing potential both as tools for basic research and therapeutic development. They occupy chemical space that lies outside the classical Lipinski 'Rule of 5', which poses fresh challenges for achieving cell permeability and oral bioavailability. This study presents a comprehensive database of degrader structures from the peer reviewed literature, including both optimized degraders and first generation compounds, in order to provide a thorough assessment of the chemical space associated with this modality and identify common trends used during the 'hit to lead' process. The results provide insights into this new area of chemical space as well as pointers for degrader design, which we anticipate will be useful for researchers entering this field.

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated "drug-likeness" properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.

Aromatic prenyltransferases from natural product biosynthetic pathways display relaxed specificity for their aromatic substrates. While a growing body of evidence suggests aromatic prenyltransferases to be more tolerant towards their alkyl-donor substrates, most studies aimed at probing their donor-substrate specificity are limited to only a small set of alkyl pyrophosphate donors, restricting their broader utility as biocatalysts for synthetic applications. Here, we assess the donor substrate specificity of an l-tryptophan C4-prenyltransferase, also known as C4-dimethylallyltryptophan synthase, FgaPT2 from Aspergillus fumigatus, using an array of 34 synthetic unnatural alkyl-pyrophosphate analogues, and demonstrate FgaPT2 can catalyze the transfer of 25 of the 34 non-native alkyl groups from their corresponding synthetic alkyl-pyrophosphate analogues at N1, C3, C4 and C5 position of tryptophan in a normal and reverse manner. The kinetic studies and regio-chemical analysis of the alkyl-l-tryptophan products suggest that the alkyl-donor transfer by FgaPT2 is a function of the stability of the carbocation and the steric factors in the active site of the enzyme. Further, to demonstrate the biocatalytic utility of FgaPT2, this study also highlights the FgaPT2-catalyzed synthesis of a small set of alkyl-diversified indolocarbazole analogues. These results reveal FgaPT2 to be more tolerant to diverse non-native alkyl-donor substrates beyond their known acceptor substrate promiscuity and set the stage for its development as a novel biocatalytic tool for the differential alkylation of natural products for drug discovery and other synthetic applications.

Several 'second-generation' click inhibitors of the multi-species biofilm propagated by the adherence of the oral pathogen Porphyromonas gingivalis to Streptococcus gordonii were synthesized and evaluated. The design of the structures was based on the results obtained with the first-generation diphenyloxazole 'click' inhibitors which bear suitable hydrophobic and polar groups within a dual scaffold molecule bearing a 1,2,3-triazole spacer. The structures of the synthetic targets reported herein now consist of a triazolyl(phenylsulfonylmethyl) and a triazolyl(phenylsulfinylmethyl) spacer which joins a 4,5-diphenyloxazole with both phenyl rings bearing lipophilic substituents. The triazolyl "linker" group is formed by a click reaction between the 4-azido(phenylsulfonyl/sulfinylmethyl) oxazoles and acetylenic components having aryl groups bearing hydrophobic substituents. The 1,3,5-trisubstituted-2,4,6-triazine scaffold of the most active click compounds were modeled after the structural motif termed the VXXLL nuclear receptor (NR) box. When substituted at the 3- and 5-positions with 2- and 4-fluorophenylamino and N,N-diethylamino units, the candidates bearing the 1,3,5-trisubstituted-2,4,6-triazine scaffold formed a substantial subset of the second-generation click candidates. Four of the click products, compounds 95, 111, 115 and 122 showed inhibition of the adherence of P. gingivalis to S. gordonii with an IC50 range of 2.3-4.3 μM and only 111 exhibited cytotoxic activity against telomerase immortalized gingival keratinocytes at 60 μM. These results suggest that compounds 95, 115, 122, and possibly 111 represent the most suitable compounds to evaluate for activity in vivo.

The syntheses of metallo-β-lactamase inhibitors comprising chelating moieties, with varying zinc affinities, and peptides partly inspired from bacterial peptide sequences, have been undertaken. The zinc chelator strength was varied using the following chelators, arranged in order of ascending binding affinity: dipicolylamine (DPA, tridentate), dipicolyl-1,2,3-triazolylmethylamine (DPTA, tetradentate) dipicolyl ethylenediamine (DPED, tetradentate) and trispicolyl ethylenediamine (TPED, pentadentate). The chosen peptides were mainly based on the known sequence of the C-terminus of the bacterial peptidoglycan precursors. Biological evaluation on clinical bacterial isolates, harbouring either the NDM-1 or VIM-2 metallo-β-lactamase, showed a clear relationship between the zinc chelator strength and restoration of meropenem activity. However, evaluation of toxicity on different cancer cell lines demonstrated a similar trend, and thus inclusion of the bacterial peptides did possess rather high toxicity towards eukaryotic cells.

The synthesis of a series of novel aza-brazilan derivatives containing imidazolium salt pharmacophores is presented. The biological activity of such imidazolium salts was further evaluated in vitro against a panel of human tumor cell lines. The results suggest that the electron-withdrawing group on the aza-brazilan moiety, substituted 5,6-dimethyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-methylbenzyl group were essential for modulating the cytotoxic activity. Compounds 55 and 39, bearing a 4-methylbenzyl substituent at position-3 of 5,6-dimethyl-benzimidazole, were found to be the most potent compounds with IC50 values of 0.52-1.30 μM and 0.56-1.51 μM against four human tumor cell lines investigated. Particularly, compound 57 exhibited inhibitory activity against the MCF-7 cell line with an IC50 value of 0.35 μM and was 56-fold more sensitive than DDP. Moreover, compound 55 inhibited cell proliferation through inducing G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells.

The macromolecule that carries genetic information, DNA, is considered as an exceptional target for diseases depending on cellular division of malignant cells (i.e. cancer), microbes (i.e. bacteria) or parasites (i.e. protozoa). To aim for a comprehensive review to cover all aspects related to DNA targeting would be an impossible task and, hence, the objective of the present review is to present, from a medicinal chemistry point of view, recent developments of compounds targeting the minor groove of DNA. Accordingly, we discuss the medicinal chemistry aspects of heterocyclic small-molecules binding the DNA minor groove, as novel anticancer, antibacterial and antiparasitic agents.

The quinolone antibiotics arose in the early 1960s, with the first examples possessing a narrow-spectrum of activity with unfavorable pharmacokinetic properties. Over time, the development of new quinolone antibiotics has led to improved analogues with an expanded spectrum and high efficacy. Nowadays, quinolones are widely used for treating a variety of infections. Quinolones are broad-spectrum antibiotics that are active against both Gram-positive and Gram-negative bacteria, including mycobacteria, and anaerobes. They exert their actions by inhibiting bacterial nucleic acid synthesis through disrupting the enzymes topoisomerase IV and DNA gyrase, and by causing breakage of bacterial chromosomes. However, bacteria have acquired resistance to quinolones, similar to other antibacterial agents, due to the overuse of these drugs. Mechanisms contributing to quinolone resistance are mediated by chromosomal mutations and/or plasmid gene uptake that alter the topoisomerase targets, modify the quinolone, and/or reduce drug accumulation by either decreased uptake or increased efflux. This review discusses the development of this class of antibiotics in terms of potency, pharmacokinetics and toxicity, along with the resistance mechanisms which reduce the quinolones' activity against pathogens. Potential strategies for future generations of quinolone antibiotics with enhanced activity against resistant strains are suggested.

In the world, among the neurodegenerative diseases, Parkinson's is the second most common disease. Although several medications are available in the market, this disease still remains incurable and only the symptoms are controlled to a certain extent with severe side effects. For these reasons we decided to search for a novel therapeutic measure. The objective of this publication was to find a therapeutic procedure to cure this devastating disease. In this study, a biocompatible, easily permeable, cationic nanoparticle-layered double hydroxide was synthesized. Within the layers of these nanoparticles we intercalated α synuclein siRNA, which helps to silence the α synuclein gene. After the intercalation, which was optimized at a 1 : 40 ratio of siRNA : (LDH), we studied its stability in blood by a RNase protection test and serum protection assay. Both proved that LDH was an excellent nanocarrier that can protect intercalated molecules within its layers. After that, several cellular studies were performed by FACS to evaluate its biocompatibility after intercalation and cellular internalization. Results of the biocompatibility studies found it to be nontoxic and in the cellular internalization study, 51.55% of cells were taken into the nanoconjugate and confocal microscopy supported the data from FACS. Lastly, ELISA was performed to discover protein levels in the control, overexpressed, and treated groups of the SH-SY5Y cell line. These results verified that this nanoconjugate is a protective treatment procedure for Parkinson's disease.

Analogues of a novel class of benzimidazoles with an intramolecular hydrogen bonding motif have been synthesized and evaluated in vitro for their antiplasmodium activity against chloroquine-sensitive (NF54) and multi-drug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. Compounds were also screened for their cytotoxicity towards a mammalian Chinese hamster ovarian (CHO) cell line. Most of the compounds exhibited good antiplasmodium activity (PfNF54 IC50 <1 μM) and were relatively noncytotoxic. Moreover, towards establishing the possible mode of action of these molecules, inhibition of beta-hematin formation was investigated and two compounds were found to be inhibitors. Single crystal X-ray data confirmed the existence of an intramolecular hydrogen bond.