CYP121A1 is a promising cytochrome P450 (CYP) drug target in Mycobacterium tuberculosis (Mtb) owing to its physiological importance in bacterial cell viability. The continuing rise of multidrug resistant (MDR) and extremely drug resistant (XDR) tuberculosis (TB), offers potential therapeutics with a new mechanism of action to add to the multidrug TB regime. A series of 3-(pyridine-3-ylmethylene)chromanone derivatives (5) with 7-O-alkyl/aryl substitutions were explored for CYP121A1 binding and antimycobacterial activity in susceptible and resistant Mtb strains. The 3-(pyridine-3-ylmethylene)chroman-4-one derivatives (5) with the 7-O-(CH2)3-phenyl substitution displayed the strongest CYP121A1 binding affinity (K D 0.3 to 3.6 μM) compared with the natural substrate (dicyclotyrosine, K D 16.8 ± 1.0 μM). Improvements observed in binding affinity from 7-O-benzyl to (CH2)2-phenyl to (CH2)3-phenyl substitutions are supported by computational studies. Minimum inhibitor concentration (MIC) of the alkyoxyaryl substituted chromanones ranged from 1.5-50 μM (0.5-22.5 μg mL-1) against the H37Rv wild type strain (c.f. isoniazid 1.8 μM (0.2 μg mL-1), rifampicin 0.3 μM (0.2 μg mL-1), kanamycin 16.1 μM (7.8 μg mL-1)) with antimycobacterial activity retained against mono-resistant (isoniazid or rifampicin) and MDR (isoniazid and rifampicin) Mtb strains. In contrast, the tetralone derivatives (8) with either the O-(CH2)2-phenyl or O-(CH2)3-phenyl substitutions showed no binding affinity with CYP121A1, possibly owing to binding further away from the haem and failing to displace the 6th axial water ligand, but the O-(CH2)3-phenyl substituted tetralones were the most consistently effective against H37Rv strain with MIC of 3 μM (1.1-1.2 μg mL-1) and retained activity against the mono-resistant and MDR Mtb strains.

The rise in fungal drug resistance has exacerbated the treatment of invasive fungal infections, most commonly caused by Candida. This research describes the synthesis of extended "long-arm" azole antifungals that were evaluated against wild-type and resistant fungal species. Biphenyl derivative 22 was the most effective derivative, displaying potent inhibitory activity against Saccharomyces, Candida, and Cryptococcus CYP51 enzymes, including in resistant strains, in comparison with posaconazole. The X-ray crystal structure of S-22 complexed with S. cerevisiae CYP51 showed a hydrogen bond between the oxygen of the trifluoromethoxy group of S-22 and the His381 side chain of S. cerevisiae CYP51, which is postulated to contribute significantly to its binding, and stabilization in the presence of the S. cerevisiae CYP51 Y140F/H, C. parapsilosis and C. auris CYP51 Y132F mutations and the C. auris K143R mutation. Computational studies and IC50 evaluation of compound 22 vs C. albicans wild-type, Y132F, and Y132H/K143 mutant strains supported MIC observations.

In electrochemical sensing platforms, monensin sodium and nonactin ionophores have been extensively used for the selective recognition of metal cations. The objective of this research is to study and compare their potential for the selective potentiometric detection of ephedrine hydrochloride, a small organic cation. Ephedrine hydrochloride was chosen because of its small molecular size and flexibility, which facilitate its incorporation and binding with ionophores. To measure the concentration of ephedrine hydrochloride, two carbon paste electrodes were designed, where monensin sodium (carbon paste electrode 1) and nonactin (carbon paste electrode 2) served as recognition elements. A combination of CuO and multiwalled carbon nanotubes was employed as an ion-to-electron transducer. The electrodes' selectivity, sensitivity, and response toward ephedrine hydrochloride were evaluated according to IUPAC guidelines. The studied electrodes showed linearity over the concentration ranges of 1 x 10-3 M to 1 x 10-5 M and x 10- 2 M to 1 x 10- 7 M with LOD values of 5 x 10-6 M and 9 x 10- 8 M, for electrodes 1 and 2, respectively. They exhibited high stability for approximately 73 and 95 days, respectively, with no surface renewal action. Both electrodes were used to measure the concentrations of ephedrine hydrochloride in spiked human plasma, pure form, and in different pharmaceutical dose forms.

Fungal infections have been described as a silent crisis affecting more than one billion people each year. At least 150 million of these cases involve severe and life threatening invasive fungal infections, accounting for approximately 1.7 million deaths annually. 1,2,4-Trizoles such as fluconazole and posaconazole are widely used antifungal agents, but azole resistance is an increasing problem requiring further study. 1,2,4-Triazole derivatives with medium and long arm extensions designed to bind within the Candida albicans CYP51 (CaCYP51) access channel were synthesised to study their inhibition of CaCYP51 (IC50, MIC) and binding affinity (K d). A long arm extension using the amide linker was found to be most effective (e.g.13), giving an antifungal profile vs. wild-type and resistant model fungal strains comparable with posaconazole.

Dual aromatase sulfatase inhibitors (DASIs) were developed from a common benzofuran pharmacophore resulting in potent low nanomolar inhibitors, which combined with molecular dynamics studies provided a clear rationale for the activity observed.

Based on a previous study from our group, fifteen new tetrahydrocarbazoles (THC) incorporating 5-arylidene-4-thiazolinone scaffolds at one position were synthesized and characterized by spectroscopic, elemental and X-ray crystallographic techniques. The new hybrids were evaluated for their anti-proliferative activity against a panel of eight human cancer cell lines utilizing Sulforhodamine B (SRB) assay with doxorubicin as a reference. Among all synthesized THC based hybrids, compounds 11c and 12c revealed the highest potency and selectivity against Jurkat (IC50 1.44 ± 0.09 μM), U937 (IC50 1.77 ± 0.08 μM) and HCT-116 (IC50 6.75 ± 0.08 μM) cell lines, while against normal cell line HME1 (IC50 > 50 μM). To validate the multitarget approach, topoisomerases, tubulin and EGFR inhibition assays were performed. Results indicate that compound 11c inhibited Topo Iα (IC50 52.12 μM), Topo IIα (IC50 57.22 μM), EGFR (IC50 0.13 μM) and tubulin polymerization (IC50 8.46 μM) in higher than or comparable potency to the appropriate reference drugs. It also arrested the cell cycle at the G0/G1 phase and induced apoptosis. Molecular dynamic analysis strongly support intercalation into DNA as a dominant binding mode of compounds 11c and 12c within the binding site of Topo Iα and Topo IIα. Moreover, molecular docking study highlights potential binding interactions of compound 11c within tubulin and EGFR active sites. These findings provide a foundation for developing multitarget anticancer agents against leukemia, lymphoma and colon cancers.

Gallic acid is a naturally occurring low molecular weight triphenolic molecule identified as a potent antioxidant, protecting against various types of reactive species and non-radicals. Three novel carbon paste electrodes were developed for the potentiometric determination of gallic acid. Azamacrocyclic ionophors; cyclen, hexacyclen, and kryptofix-22 were utilized as recognition ionophores separately. A multi-walled carbon nanotubes/titanium oxide nanocomposite was employed as the ion-to-electron transducer in the designed sensors. The prepared transducer was characterized by FT-IR and TEM. Molecular docking was implemented to study the recognition mechanism between these ionophores and the gallic acid molecule. It revealed promising binding interactions between gallic acid and the three recognition ionophores, especially hexacyclen and Kryptofix-22. In studying the potentiometric response of the proposed sensors, they exhibited high stability, sensitivity, accuracy, and precision in the quantitation of gallic acid. Gallic acid can be accurately quantified over the linearity range of 1 x 10-- 1 - 1 x 10-3-3 M, 1 x 10-- 2 - 1 x 10-- 6 M, and 1 x 10-- 2 - 1 x 10-6-6 M with a Limit of detection (LOD) 4 x 10-4-4 M, 3 x 10-- 7 M, and 7 x 10-- 7 M, for CPE1, CPE 2 and CPE 3, respectively. The electrodes showed high efficiency in determining gallic acid in Krameria lappacea root alcoholic extract, black tea, green tea, and human plasma without sophisticated pretreatment steps.

Currently, the treatment of Proteus mirabilis infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS), a member of the aminoacyl-tRNA synthetase family, is essential for protein biosynthesis offering a promising target for novel antibiotics discovery. In the context of computer-aided drug design (CADD), the current research presents the construction and analysis of a comparative homology model for P. mirabilis MetRS, enabling development of novel inhibitors with greater selectivity. Molecular Operating Environment (MOE) software was used to build a homology model for P. mirabilis MetRS using Escherichia coli MetRS as a template. The model was evaluated, and the active site of the target protein predicted from its sequence using conservation analysis. Molecular dynamic simulations were performed to evaluate the stability of the modeled protein structure. In order to evaluate the predicted active site interactions, methionine (the natural substrate of MetRS) and several inhibitors of bacterial MetRS were docked into the constructed model using MOE. After validation of the model, pharmacophore-based virtual screening for a systemically prepared dataset of compounds was performed to prove the feasibility of the proposed model, identifying possible parent compounds for further development of MetRS inhibitors against P. mirabilis.

Aromatase (CYP19A1) inhibitors are the mainstay therapeutics for the treatment of hormone dependant breast cancer, which accounts for approximately 70% of all breast cancer cases. However, increased resistance to the clinically used aromatase inhibitors, including letrozole and anastrazole, and off target effects, necessitates the development of aromatase inhibitors with improved drug profiles. The development of extended 4th generation pyridine based aromatase inhibitors with dual binding (haem and access channel) is therefore of interest and here we describe the design, synthesis and computational studies. Cytotoxicity and selectivity studies identified the pyridine derivative (4-bromophenyl)(6-(but-2-yn-1-yloxy)benzofuran-2-yl)(pyridin-3-yl)methanol (10c) as optimal with CYP19A1 IC50 0.83 nM (c.f. letrozole IC50 0.70 nM), and an excellent cytotoxicity and selectivity profile. Interestingly, computational studies for the 6-O-butynyloxy (10) and 6-O-pentynyloxy (11) derivatives identified an alternative access channel lined by Phe221, Trp224, Gln225 and Leu477, providing further insight into the potential binding mode and interactions of the non-steroidal aromatase inhibitors.

The development of novel antimycobacterial agents is an urgent challenge to eradicate the increasing emergence and rapid spread of multidrug-resistant strains. Filamentous temperature-sensitive protein Z (FtsZ) is a crucial cell division protein. Alteration of FtsZ assembly leads to cell division inhibition and cell death. To find novel antimycobacterial agents, a series of N1 -(benzo[d]oxazol-2-yl)-N4 -arylidine compounds 5a-o were synthesized. The activity of the compounds was evaluated against drug-sensitive, multidrug-resistant, and extensive-drug-resistant Mycobacterium tuberculosis. Compounds 5b, 5c, 5l, 5m, and 5o showed promising antimycobacterial activity with minimum inhibitory concentrations (MIC) in the range of 0.48-1.85 µg/mL and with low cytotoxicity against human nontumorigenic lung fibroblast WI-38 cells. The activity of the compounds 5b, 5c, 5l, 5m, and 5o was evaluated against bronchitis causing-bacteria. They exhibited good activity against Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumonia, and Bordetella pertussis. Molecular dynamics simulations of Mtb FtsZ protein-ligand complexes identified the interdomain site as the binding site and key interactions. ADME prediction indicated that the synthesized compounds have drug-likeness. The density function theory studies of 5c, 5l, and 5n were performed to investigate E/Z isomerization. Compounds 5c and 5l are present as E-isomers and 5n as an E/Z mixture. Our experimental outcomes provide an auspicious lead for the design of more selective and potent antimycobacterial drugs.

Antimicrobial resistance is a very challenging medical issue and identifying novel antimicrobial targets is one of the means to overcome this challenge. Phenylalanyl tRNA synthetase (PheRS) is a promising antimicrobial target owing to its unique structure and the possibility of selectivity in the design of inhibitors. Sixteen novel benzimidazole based compounds (5a-b), (6a-e), (7a-d), (9a-e) and three N,N-dimethyl-7-deazapurine based compounds (16a-c) were designed to mimic the natural substrate of PheRS, phenylalanyl adenylate (Phe-AMP), that was examined through flexible alignment. The compounds were successfully synthesised chemically in two schemes using 4 to 6-steps synthetic pathways, and evaluated against a panel of five microorganisms with the best activity observed against Enterococcus faecalis. To further investigate the designed compounds, a homology model of E. faecalis PheRS was generated, and PheRS-ligand complexes obtained through computational docking. The PheRS-ligand complexes were subjected to molecular dynamics simulations and computational binding affinity studies. As a conclusion, and using data from the computational studies compound 9e, containing the (2-naphthyl)-l-alanine and benzimidazole moieties, was identified as optimal with respect to occupancy of the active site and binding interactions within the phenylalanine and adenosine binding pockets.

One in every eight women will be diagnosed with breast cancer during their lifetime and approximately 70% of all patients are oestrogen receptor (ER) positive depending upon oestrogen for their growth accounting for third generation aromatase (CYP19A1) inhibitors being the mainstay in the treatment of ER-positive breast cancer. Despite the success of current aromatase inhibitors, acquired resistance occurs after prolonged therapy. Although the precise mechanisms of resistance are not known, lack of cross resistance among aromatase inhibitors drives the need for a newer generation of inhibitors to overcome this resistance alongside minimising toxicity and adverse effects. Novel triazole-based inhibitors were designed based on previously published parent compound 5a, making use of the now available crystal structure of CYP19A1 (PDB 3S79), to make modifications at specific sites to explore the potential of dual binding at both the active site and the access channel. Modifications included adding long chain substituents e.g. but-2-ynyloxy and pent-2-ynyloxy at different positions including the most active compound 13h with IC50 value in the low picomolar range (0.09 nM). Aromatase inhibition results paired with molecular dynamics studies provided a clear structure activity relationship and favourable dual binding mode was verified. Toxicity assays and CYP selectivity profile studies for some example compounds were performed to assess the safety profile of the prepared inhibitors providing the basis for the 4th generation nonsteroidal aromatase inhibitors.

Topoisomerase (IIB) inhibitors have been involved in the therapies of tumour progression and have become a major focus for the development of anticancer agents. New three-component hybridised ligands, 1,4-disubstituted-1,2,3-triazoles (8–17), were synthesised via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine/3-azidocoumarin with N/O-propargyl small molecules under click reaction conditions. Cancer cell growth inhibition of the synthesised triazoles was tested against human cell-lines in the NCI-60-cell-panel, and the most active compounds tested against topoisomerase (IIB)-enzymes. The acridinyl ligands (8–10) revealed 60–97% cell growth inhibition in six cancer cell-panels. Cell-cycle analysis of MCF7 and DU-145 cells treated with the active acridinyl ligands exhibited cell-cycle arrest at G2/M phase and proapoptotic activity. In addition, compound 8 displayed greater inhibitory activity against topoisomerase (IIB) (IC50 0.52 µM) compared with doxorubicin (IC50 0.83 µM). Molecular dynamics simulation studies showed the acridine–triazole–pyrimidine hybrid pharmacophore was optimal with respect to protein–ligand interaction and fit within the binding site, with optimal orientation to allow for intercalation with the DNA bases (DG13, DC14, and DT9).

A series of imidazole and triazole diarylpyrazole derivatives were prepared using an efficient 5-step synthetic scheme and evaluated for binding affinity with Mycobacterium tuberculosis (Mtb) CYP121A1 and antimycobacterial activity against Mtb H37Rv. Antimycobacterial susceptibility was measured using the spot-culture growth inhibition assay (SPOTi): the imidazoles displayed minimum inhibitory concentration (MIC90) in the range of 3.95-12.03 μg mL-1 (10.07-33.19 μM) with 11f the most active, while the triazoles displayed MIC90 in the range of 4.35-25.63 μg mL-1 (11.88-70.53 μM) with 12b the most active. Assessment of binding affinity using UV-vis spectroscopy showed that for the imidazole series, the propyloxy (11f) and isopropyloxy (11h) derivatives of the 4-chloroaryl pyrazoles displayed Mtb CYP121A1 type II binding affinity with Kd 11.73 and 17.72 μM respectively compared with the natural substrate cYY (Kd 12.28 μM), while in the triazole series, only the methoxy substitution with the 4-chloroaryl pyrazole (12b) showed good type II Mtb CYP121A1 binding affinity (Kd 5.13 μM). Protein-detected 1D 19F-NMR spectroscopy as an orthogonal strategy was used to evaluate ligand binding independent of perturbations at the haem. For imidazole and triazole compounds, perturbations were more intense than cYY indicating tighter binding and confirming that ligand coordination occurs in the substrate-binding pocket despite very modest changes in UV-vis absorbance, consistent with computational studies and the demonstrated potential anti-tuberculosis properties of these compounds.

Invasive fungal infections have increased in frequency and severity over the last twenty years as a result of an increasing number of immunocompromised hosts due to cancer chemotherapy, organ and bone marrow transplantation, or therapy against autoimmune and inflammatory disorders. Candida species (spp.) are among the most common pathogens. Candida albicans is the main cause of candidiasis. In addition non-albicans Candida spp. are becoming more and more involved in nosocomial infections. The emergence of resistance to conventional treatments (e.g. fluconazole) make healing successes weaker. It is therefore urgent to continue efforts to develop new antifungal agents. A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole by replacing one of its two triazole moieties by an indole scaffold. Two different chemical pathways were developed; the first one included seven steps and the second one only three. The pharmacomodulation works have enabled us to identify a molecule with a strong biological impact on fungi. Numerous experiments progressively confirmed the high potential of this hybrid molecule as antifungal agent. In this presentation, all aspects of medicinal chemistry will be addressed.

Background Two series of benzimidazole based thio-oxadiazole and thio-thiadiazole analogues were designed and synthesised as novel antimicrobial drugs through inhibition of phenylalanyl-tRNA synthetase (PheRS), which is a promising antimicrobial target. Compounds were designed to mimic the structural features of phenylalanyl adenylate (Phe-AMP) the PheRS natural substrate. Methods A 3D conformational alignment for the designed compounds and the PheRS natural substrate revealed a high level of conformational similarity, and a molecular docking study indicated the ability of the designed compounds to occupy both Phe-AMP binding pockets. A molecular dynamics (MD) simulation comparative study was performed to understand the binding interactions with PheRS from different bacterial microorganisms. The synthetic pathway of the designed compounds proceeded in five steps starting from benzimidazole. The fourteen synthesised compounds 5a - d , 6a - c , 8a - d and 9a - c were purified, fully characterised and obtained in high yield. Results In vitro antimicrobial evaluation against five bacterial strains showed a moderate activity of compound 8b with MIC value of 32 μg/mL against S. aureus , while all the synthesised compounds showed weak activity against both E. faecalis and P. aeruginosa (MIC 128 μg/mL). Conclusion Compound 8b provides a lead compound for further structural development to obtain high affinity PheRS inhibitors.

Tuberculosis is caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) and remains the leading cause of death by infection world-wide. The Mtb genome encodes a disproportionate number of twenty cytochrome P450 enzymes, of which the essential enzyme cytochrome P450 121A1 (CYP121A1) remains a target of drug design efforts. CYP121A1 mediates a phenol coupling reaction of the tyrosine dipeptide cyclo-L-Tyr-L-Tyr (cYY). In this work, a structure and function investigation of dimerization was performed as an overlooked feature of CYP121A1 function. This investigation showed that CYP121A1 dimers form via intermolecular contacts on the distal surface and are mediated by a network of solvent-exposed hydrophobic residues. Disruption of CYP121A1 dimers by site-directed mutagenesis leads to a partial loss of specificity for cYY, resulting in an approximate 75% decrease in catalysis. 19 F labeling and nuclear magnetic resonance of the enzyme FG-loop was also combined with protein docking to develop a working model of a functional CYP121A1 dimer. The results obtained suggest that participation of a homodimer interface in substrate selectivity represents a novel paradigm of substrate binding in CYPs, while also providing important mechanistic insight regarding a relevant drug target in the development of novel anti-tuberculosis agents.

Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. In vivo, retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid (RA) pharmacokinetics in pre-clinical neuroblastoma models. Here, we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance RA action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here, we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signalling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans.

Fungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasiveCandidainfections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals inC. albicansposes a threat to public health. Two series of novel azole derivatives, short and extended derivatives, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) againstC. albicansstrains. The short derivatives were more potent against theC. albicansstrains (e. g., MIC 2-(4-chlorophenyl)-N-(2,4-dichlorobenzyl)-3-(1H-imidazol-1-yl)propanamide (5 f) <0.03 mu g/mL,N-(4-((4-chlorophenyl)sulfonamido)benzyl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propanamide (12 c), 1 mu g/mL, fluconazole 0.125 mu g/mL) but both displayed comparable enzyme binding and inhibition (5 fK(d)62 +/- 17 nM, IC(50)0.46 mu M;12 cK(d)43 +/- 18 nM, IC(50)0.33 mu M, fluconazoleK(d)41 +/- 13 nM, IC(50)0.31 mu M, posaconazoleK(d)43 +/- 11 nM, IC(50)0.2 mu M). The short series had poor selectivity for CaCYP51 over the human homologue, whereas the selectivity of the extended series, for example, compound12 c, was higher (21.5-fold) than posaconazole (4.7-fold) based onK(d)values, although posaconazole was more selective (615-fold) than12 c(461-fold) based on IC(50)values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development.

A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed by X-ray diffraction to determine their absolute configuration. The (−)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC80 = 0.000256 µg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 µg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 µg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (−)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated.