Most fungal infections are common, localized to skin or mucosal surfaces and can be treated effectively with topical antifungal agents. However, while invasive fungal infections (IFIs) are uncommon, they are very difficult to control medically, and are associated with high mortality rates. We have previously described highly potent bis-guanidine-containing heteroaryl-linked antifungal agents, and were interested in expanding the range of agents to novel series so as to reduce the degree of aromaticity (with a view to making the compounds more drug-like), and provide broadly active high potency derivatives. We have investigated the replacement of the central aryl ring from our original series by both amide and a bis-amide moieties, and have found particular structure-activity relationships (SAR) for both series’, resulting in highly active antifungal agents against both mold and yeast pathogens. In particular, we describe the in vitro antifungal activity, absorption, distribution, metabolism and elimination (ADME) properties, and off-target properties of FC12406 (34), which was selected as a pre-clinical development candidate.

A series of novel 4,6,7-trisubstituted quinazoline derivatives containing benzothiazole moiety were designed, synthesized and evaluated for their antitumor activity against four human cancer cells (PC-3, MGC-803, A549 and Eca-109) using MTT assay. Among them, compound 11k showed the most potent cytotoxicity against PC-3 cells (IC50 = 5.59 ± 0.78 μM). Compound 11k also significantly inhibited the colony formation and migration of PC-3 cells. Meanwhile, compound 11k induced cell cycle arrest at S-phase and cell apoptosis, as well as increased accumulation of intracellular reactive oxygen species. All the findings suggest that compound 11k might be a valuable lead compound for anti-tumor agents targeting prostate cancer cells.

In the current study, a series of pyrimidine derivatives containing the 4-hydroxypiperidine group were designed and synthesized, and the antiproliferative activity of these compounds against four human tumor cell lines (MGC-803, PC-3, A549, H1975) was evaluated by MTT method in vitro. Most of the compounds have moderate anti-proliferative activities, among which compound 17i displayed the most excellent anti-proliferative activity, with IC50 value of 3.89 ± 0.57 µM against H1975 cell. Preliminary antitumor mechanism studies revealed that compound 17i could inhibit colony formation and cell migration of H1975 cells. Furthermore, compound 17i induced H1975 cells apoptosis in a dose-dependent manner and H1975 cell cycle arrest in S phase to inhibit cell proliferation. These results indicates that compound 17i could be a promising lead for further studies.Graphical Abstract

A series of tetrasubstituted pyrimidine derivatives containing methyl phenyl sulfone structure were designed, synthesized and evaluated for antiproliferative activity against four human cancer cell lines of MGC-803, Eca-109, PC-3 and MCF-7 using methyl thiazolyl tetrazolium (MTT) assay. Most of the compounds displayed moderate to excellent antiproliferative activity against the four human tumor cell lines, among which the compound 27g showed the best antiproliferative activity on MGC-803 cells, with IC50 value of (2.98 ± 0.13) μM, which is significantly better than that of the positive control 5-FU. Further studies on the anti-tumor mechanism showed that compound 27g significantly inhibited colony formation and migration of MGC-803 cells, blocked the cell cycle in GO/G1 phase, and induced apoptosis.Graphical Abstract

Galectin proteins have been targets of interest in numerous therapeutic areas for some time. Galectin-3 has been identified as a target of particular interest because of its unique structural characteristics and physiological profile. Recent literature indicates galectin-3 inhibition can decrease myofibroblast activation and procollagen expression with the potential to affect the progression of fibrosis in the lung, liver and kidney. Potential π-stacking interactions between one monosaccharide ligand bound to the carbohydrate recognition domain of a galectin-3 protein and a second ligand bound to a different galectin-3 protein molecule were observed in the extended crystalline lattice in an X-ray crystal structure obtained while studying the monosaccharide structure-activity relationship. The direct interaction between the ligands suggests a potential for dimeric galectin-3 inhibitors which bind to two galectin-3 molecules simultaneously. This work describes the exploration of dimers designed to further probe these observations and explore the potential of binding to dimeric or higher order multimeric galectin-3 assemblies.

Coumarin-pyrimidine hybrid compounds were synthesized by condensation reaction of α,β-unsaturated ketones of 6-acetyl-5-hydroxy-4-methylcoumarin with guanidine. The reaction yields were of 42–62%. The antidiabetic and anticancer activities of these compounds were examined. These compounds displayed low toxicity to two cancer cell lines (including KB and HepG2 ones), but exhibited remarkably active against α-amylase with IC50 values of 102.32 ± 1.15 μM to 249.52 ± 1.14 μM and against α-glucosidase with IC50 values of 52.16 ± 1.12 μM to 184.52 ± 1.15 μM. Amongst these compounds, 6c was the best inhibitory activity against α-amylase, and 6f had the highest activity against α-glucosidase. The kinetics of inhibitor 6f was competitive α-glucosidase inhibitor property. ADMET predictions showed that almost all synthesized compounds exhibited drug-like activity. IFD and MD simulations were carried out on enzymes 4W93 and 5NN8 to elucidate inhibitory potential of 6c and 6f against tested enzymes. The binding free energy calculation by MM-GBSA approach showed that Coulomb, lipophilic and van der Waals energy terms are major contributors for the inhibitor binding. Molecular dynamics simulations in water solvent system were carried out for the 6f/5NN8 complex to elucidate the variability of active interactions between ligand 6f and active pockets of this enzyme.Graphical Abstract

Two series of new 1,2,3-triazole-purine hybrids were synthesized in considerable yields (up to 87%), starting from benzyl azides and purine alkynes, via 1,3-dipolar cycloaddition reaction catalyzed with Cu(I). The first (7a-k) and second (8a-k) series of hybrids employed kinetin and adenine as precursors, respectively. All synthesized compounds were evaluated in vitro for their antiproliferative activity against two breast cancer cell lines (MCF-7 and MDA-MB-231) and a non-tumor cell line (MCF-10A) to estimate their selectivity. From the twenty-two synthesized compounds, eight (4, 7a-e, 7 h and 8a) were active against both tumor cell lines, especially the kinetin derivatives, which displayed better results than the adenine derivatives. The original kinetin molecule was not active, suggesting that structural changes in its derivatives were favorable to induce cytotoxic effects in the tested cells. Compounds 7c and 7d were the most active, with IC50 of 22.3 µM and 22.9 µM for MCF-7, and IC50 of 9.3 µM and 16.7 µM for MDA-MB-231, respectively. In addition, the ADMET in silico study indicated that the active compounds (4, 7a-e, 7 h and 8a) presented drug-like similarities and a potential use as anticancer agents.Graphical Abstract

Tuberculosis is an infectious disease that has re-emerged in multiple/extensively resistant forms (MDR/XDR) since 1990’s creating threat to the mankind. The marketed drugs are not fully effective on these forms as they suffer from serious side effects. Thus developing drugs targeting the novel targets is the need of the hour to treat the disease. Many novel targets have been identified and Polyketide synthase 13 (Pks 13) has emerged as one of the promising targets to treat the tuberculosis. It links the meromycolic acid (C48-C64) branch originating from FAS-II, and α -alkyl C26 fatty acid branch originating from fatty acid synthase I (FAS-I) via Claisen condensation and helps in final formation of precursors of mycolic acid, the major component of Cell walls of M. tuberculosis. It has five domains viz Acyl Carrier Protein -Keto acyl Synthase-Acetyl Tranferase-Acyl Carrier Protein-Thioesterase [ACP-KS-AT-ACP-TE]. The ACP domain has two portions and one of them is adjacent to KS domain (N- terminal ACP) and C-terminal ACP resides beside of TE domain. The N-ACP domain and TE domains have active sites. Thus, efforts are made to design, synthesize and test the Novel Chemical Entities (NCE’s) for their antitubercular activity with Pks 13 enzyme as a target. The benzofurans, thiophenes, coumestans and β lactones have been identified as ligands blocking Pks 13 enzyme with promising antitubercular activity. This article summarizes these classes of Pks 13 enzyme inhibitors exhibiting potential antitubercular activity along with their limitations and discusses the future scope.Graphical Abstract

Starting from compound 5 (CCF0058981), a structure-based optimization of the P1 subsite was performed against the severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). Inhibitor 5 and the compounds disclosed bind to 3CLpro using a non-covalent mode of action that utilize a His163 H-bond interaction in the S1 subpocket. In an effort to examine more structurally diverse P1 groups a number of azoles and heterocycles were designed. Several azole ring systems and replacements, including C-linked azoles, with similar or enhanced potency relative to 5 were discovered (28, 29, and 30) with demonstrated IC50 values <100 nM. In addition, pyridyl and isoquinoline P1 groups were successful as P1 replacements leading to 3-methyl pyridyl 36 (IC50 = 85 nM) and isoquinoline 27 (IC50 = 26 nM). High resolution X-ray crystal structures of these inhibitors were utilized to confirm binding orientation and guide optimization. These findings have implications toward antiviral development and preparedness to combat SARS-like zoonotic coronavirus outbreaks.Graphical Abstract

In this study, a series of novel quinazoline/phenylsulfonylfuroxan hybrids were designed, synthesized, and biologically evaluated against five human cancer cell lines (H1975, MCF-7, Eca-109, MGC-803 and A549). The most of hybrids displayed considerable antiproliferative activities against the tested five cancer cells, while compound 25q exhibited the most potent antiproliferative activity with the IC50 values of 1.67 and 1.88 μM against H1975 cells and MGC-803 cells, respectively. Further in vitro mechanistic studies showed that 25q had the remarkable capacity to suppress the migration of H1975 cells. Besides, 25q also arrested the H1975 cell cycle in the G0/G1 phase and mediated cell apoptosis. NO releasing assay confirmed that the designed hybrids could generate a significant amount of NO and the consistent tendency between NO releasing abilities and antiproliferative activities. Among these compounds, 25q also exhibited the most potent NO releasing ability. Overall, all these studies indicate that the designed quinazoline/phenylsulfonylfuroxan hybrids have significant anti-tumor activities and excellent NO releasing ability and 25q has the potential to act as a valuable lead compound for the development of anti-tumor agents.Graphical Abstract

Using molecular hybridization and bioisosteric replacement approaches, novel agents with potential use for the treatment of Alzheimer’s disease (AD) were developed based on the structure of donepezil. A series of 14 indanone-chalcones bearing ester group were designed, synthesized, and then characterized using variety of methods. All target compounds showed moderate acetylcholinesterase (AChE) inhibitory potencies and among them, the most active compound 8e exhibited inhibitory activity with IC50 value of 18.7 µM against AChE. Also, Aβ1–40 aggregation inhibitory activities of the synthesized compounds were evaluated, and the results showed that compound 8h was able to inhibit Aβ1–40 aggregation by 81.6%. The results of docking studies revealed that some of compounds fits well into the binding site of AChE. The most active AChE inhibiting derivative 8e has close physico-chemical properties to donepezil (reference compound) and passed more drug likeness filters relative to the reference compound. Collectively, the current study provides insight for designing drug size molecules with ester group to target acetylcholinesterase in the process of developing new active compounds for AD.Graphical Abstract

Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase and an attractive anti-fibrotic target. To identify novel DDR1 inhibitors, we used an integrated lead-finding approach relying in parallel on structure-based hybrid design and a focused screening campaign. Combining structural elements from both approaches allowed us to quickly overcome several compound liabilities and optimize the hits to advanced lead compounds. Despite a very high sequence conservation between DDR1 and DDR2, we were able to identify potent DDR1 inhibitors with close to 1000-fold selectivity against DDR2 as well as good selectivity against the full kinome. Exploitation of a DDR1 selectivity pocket detected by structural bioinformatics was crucial in the optimization process. Compounds with very high selectivity suffered from poor metabolic stability in rodents but may serve as useful DDR1-selective in vitro tool molecules.Graphical Abstract

In the present study, some new 1,2,3-triazole-tethered analogs of N-northebaine were designed and synthesized. The anti-bacterial properties of novel thebaine derivatives were studied on Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Based on the results, compounds 5b, 5j and 5m showed the best activities against S. aureus (minimum inhibitory concentration (MIC) ~ 25 μM) compared to the parent compound (MIC ~ 321 μM). The most active anti-bacterial derivatives (i.e., 5b, 5j and 5m) and thebaine were considered as potent anti-bacterial wound healing agents. In this regard, fibroblast cell cytotoxicity and proliferation as well as anti-hemolytic activities of the mentioned compounds were studied. The cytotoxicity assay by using 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide (MTT) on human dermal fibroblast cell lines (HDF) revealed that products 5j and 5m didn’t show inhibition of cell line growth after 24 h. Based on the investigation results on blood cell disruption for releasing of hemoglobin, compound 5j didn’t exhibit any hemolysis activity in different doses.Graphical Abstract

We report here the discovery and structure-guided optimization of a novel series of AKT kinase inhibitors. Based on docking studies for the predicted active bound-conformation of 2, a potent series of N-substituted-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amines was developed. Compounds in the series achieve AKT pathway inhibition in cancer cells, as measured by inhibition of pathway proteins pGSK and pFKHR. Compound 12 was further evaluated in a single dose PK/PD in vivo study in tumor-bearing mice and demonstrated inhibition of phosphorylation of the direct substrate GSK and pathway biomarker S6.

Lumazine, a nitrogen-containing heterocycle, is ubiquitous and serves as a significant bio-precursor in living cells. Additionally, it can be found in multiple natural products that exhibit intriguing activities. We report here a versatile and straightforward total synthesis of a series of lumazine peptides. Fluorescence titration experiments validate the metal binding characteristics of the synthesized compounds to Fe (III) and weak to no affinities to Cu (II), Co (II), and Mn (II).Graphical Abstract

To investigate the chemical constituents of Eupatorium adenophorum Spreng. (syn. Ageratina adenophora (Spreng.) R.M. King & H. Rob.) growing in Vietnam, the water-soluble fraction from the leaf methanol extract was fractionated by column chromatography. A new sesquiterpenoid, named adenophorone (1), was isolated along with 11 known compounds (2-12). The interpretation of HR-MS and 1D and 2D NMR spectroscopic data together with experimental and theoretical ECD calculations established the absolute stereostructure of compound 1. Two isolated flavonol glucosides 9 and 10 were subjected to enzyme inhibition assays. Gossypetin 5-O-(6′′-(E)-caffeoyl)-β-D-glucopyranoside (9) inhibited α-glycosidase activity with an IC50 value of 24.0 ± 1.61 μg/mL (80% inhibition at 256 μg/mL) and acetylcholinesterase activity with an IC50 value of 217.60 ± 15.47 μg/mL (54% inhibition at 256 μg/mL). Quercetagetin 7-O-β-D-glucopyranoside (10) slightly inhibited the two enzymes (27% and 34% inhibition, respectively) at the maximal tested concentration of 256 μg/mL. The present study is the first report on the chemical constituents of the water-soluble fraction of E. adenophorum. The study also provides some evidence for the α-glycosidase and acetylcholinesterase activities of the rare polyhydroxyflavonol acylglycoside gossypetin 5-O-(6′′-(E)-caffeoyl)-β-D-glucopyranoside.

In this review, we trace origins of the joint initiative of the pharmaceutical industry and major regulatory authorities to provide a framework for the identification, quantification, and testing of drug metabolites (i.e., Metabolites in Safety Testing; MIST). Dr. Tom Baillie was hugely instrumental in initiating and guiding this process and continues to be influential in this area up to present day. Current industry approaches to MIST are described, including evolution in techniques for metabolite identification, measurement, and characterization, plus a survey of contemporary technologies used to assess whether human metabolites are disproportionate and thus may require standalone safety assessment, clinical pharmacology, and PK/PD studies. The multiple steps involved with nonclinical safety assessment of metabolites formed in humans to a greater extent than animals are covered, which leads to frequently unnecessary safety assessment of stable circulating human metabolites. Two recent case studies of marketed drugs are included, where it is shown that additional nonclinical safety assessment of disproportionate human metabolite(s) did not appear to provide useful information relevant to human safety. This retrospective also addresses impact of MIST guidance on overall drug safety, including relative contributions of on- vs. off-target activity of parent drug vs. reactive human metabolites leading to idiosyncratic toxicity for a series drugs withdrawn from the US market since 1980. The special case of metabolite involvement in developmental and reproductive toxicity profile is described. The manuscript concludes with discussion of how MIST guidelines over the last 20 years have likely impacted on industry productivity for new molecular entities.

The role of acyl glucuronide (AG) metabolites as mediators of drug-induced toxicities remains controversial, in part due to difficulties in studying this group of reactive drug conjugates. Confounding factors include the bioactivation of carboxylic acid drugs by alternative pathways, AG-mediated inhibition of key enzymes and transporters, and unanticipated interactions with several biological systems. These issues, together with the inherent instability of AGs under physiological conditions, have led to significant challenges in assessing the human safety of AGs according to current regulatory guidances. Despite important advances in the analytical methodology used to detect, identify and quantify AGs in biological fluids and tissues, there is a lack of information on the molecular mechanisms that underlie the toxicity of carboxylic acid-containing drugs and their AG metabolites. This review summarizes the current status of the field, and the de-risking strategies that have been adopted to minimize the likelihood of AG-mediated toxicity in drug discovery and lead optimization programs.

Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing the risk of idiosyncratic toxicities caused by the permanent modification of proteins, which leads to higher levels of potential haptens. Herein, we systematically review electrophilic warheads employed during the development of reversible covalent drugs. We hope the structural insights of electrophilic warheads would provide helpful information to medicinal chemists and aid in designing covalent drugs with better on-target selectivity and improved safety.Graphical Abstract