Unsubstituted Analogues Research Articles

Ancillary Ligand Steric Effects and Cyclometalating Ligand Substituents Control Excited-State Decay Kinetics in Red-Phosphorescent Platinum Complexes.

Achieving high-efficiency red phosphorescence remains a significant challenge, especially in cyclometalated platinum complexes where radiative rates are inherently slower than their iridium counterparts. In this work, six red-emitting cyclometalated platinum complexes of the formula Pt(C∧N)[(Ar)acNac] (C∧N is the cyclometalating ligand, and (Ar)acNac is an aryl-substituted β-ketoiminate ancillary ligand) were synthesized and characterized. Two C∧N ligands were employed, 1-phenylisoquinoline (piq) and its cyano-substituted analogue 1-phenylisoquinoline-4-carbonitrile (piqCN), which both result in red phosphorescence in cyclometalated platinum complexes. These were paired with three (Ar)acNac ligands that are sterically differentiated via the N-aryl group, which is phenyl in the unsubstituted analogue (Ph)acNac and 2,6-dimethylphenyl or 2,6-diisopropylphenyl in the sterically encumbered analogues. An in-depth photophysical analysis of all compounds was performed and compared to the related compounds with the acetylacetonate (acac) ancillary ligand. While quantum yields are modest in the unsubstituted (Ph)acNac complexes, steric bulk on the β-ketoiminate has a pronounced effect on the excited-state dynamics and can lead to photoluminescence quantum yields of more than 0.50 in both solution and transparent polymer films, with the photoluminescence λmax ∼ 630 nm. We show that both steric effects on the electron-rich β-ketoiminate ancillary ligands and the cyano substituent on the cyclometalating ligand play a role in achieving high-efficiency phosphorescence in the red region.

Exploring Spectral and Electrochemical Behavior of Hydroxy‐N‐Benzylideneanilines by Integrated Theoretical and Experimental Approaches

ABSTRACTThe present work explored the effect of –OH group substitution (o/p) on the spectral and electrochemical behavior of N‐benzylideneaniline. The geometry optimization of unsubstituted and (o/p)‐OH‐substituted analogs revealed the coplanarity of the molecules. The vibrational spectra of the compounds were computed using density functional theory (DFT) and compared with the experimental data. The observed bands were assigned based on total energy distribution (TED). Predicted electronic absorption spectra from time‐dependent density functional theory (TD‐DFT) calculation were compared with the UV–visible spectra of the molecules. The analysis of the lowest spin‐allowed (singlet‐singlet) excited states divulged possible electronic transition. The o‐substituted benzylideneaniline possessed the lowest highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) energy gap among the substituted and unsubstituted analogs. The intramolecular contacts were interpreted using natural bond orbital and localized molecular orbital analysis. The –CH=N– linkage was investigated as a bridge for the electron delocalization from the donor to acceptor moieties. The manifestation of a reduction peak in the cyclic voltammetric studies confirmed the electrochemical behavior in the –OH‐substituted molecule, which was diffusion‐controlled. The discrepancy in the electrochemical property concerning the position of the –OH substituent of the candidate molecules was put forward.

Halogen Bonding Hot Spots as a Constraint in Virtual Screening: A Case Study of 5-HT7R.

The recently developed and used molecular modeling approach to search for privileged amino acids for halogen bonding (XB hot spots) through XSAR sets has been applied to 5-HT7R. Herein, among all identified 5-HT7R XB hot spots, the S5x42 was employed in a virtual screening protocol as a constraint. Through a designed virtual screening protocol, 63 XSAR sets (156 compounds) were selected from more than 8 million commercially available compounds and examined using in vitro assay toward 5-HT7R. A 68% accuracy was found in predicting halogenated derivatives with higher affinity for 5-HT7R than their unsubstituted analogs. Moreover, it was observed that a halogen bond formed between S5x42 and a chlorine atom at the 3-position of the arylpiperazine fragment caused the most remarkable, 35.4-fold increase in binding affinity for 5-HT7R when compared to the nonhalogenated analog. Interestingly, molecular dynamics simulations showed the formation of a bifurcated halogen bond with S5x42.

Candidaantarctica Lipase B mediated kinetic resolution: A sustainable method for chiral synthesis of antiproliferative β-lactams

Biocatalysis is a valuable industrial approach in active pharmaceutical ingredient (API) manufacturing for asymmetric induction and synthesis of chiral APIs. Herein, we investigated synthesis of a panel of microtubule-destabilising antiproliferative β-lactam enantiomers employing a commercially available immobilised Candida antarctica lipase B enzyme together with methanol and MTBE. The β-lactam ring remained intact during chiral kinetic resolution reactions, plausibly due to a bulky N-1 phenyl substituent on the β-lactam ring substrate. The predominant reaction mediated by CAL-B was methanol catalysed conversion of the β-lactam 3-acetoxy substituent to a 3-hydroxyl group, with preferential methanolysis of the 3S, 4S enantiomer. The unreacted substrate underwent progressive enantioenrichment to the 3R, 4R enantiomer. Substitution patterns on the B ring C3 meta position of the β-lactam scaffold greatly affected the rate of reaction. Halo substituents (fluoro-, chloro- and bromo-) reduced the rate of conversion compared to unsubstituted analogues, which in turn increased enantiomeric excess (ee). Ee values up to 86 % for the 3S, 4S 3-hydroxyl enantiomer were achieved. A double resolution approach for unreacted substrate yielded high ee values (>99 %) for the 3R, 4R 3-acetoxy enantiomer. CAL-B mediated methanolysis is a more sustainable method for resolution of racemic antiproliferative β-lactams compared to a previous technique of chiral diastereomeric resolution. Yields of β-lactams obtained using CAL-B are far superior than previously described, which will facilitate progression toward pre-clinical and clinical development. Biocatalysis is a useful tool in the toolbox of the medicinal chemist.

Thermodynamics of Reversible Hydrogen Storage: Are Methoxy‐Substituted Aromatics better through Oxygen Functionality?

AbstractAn attractive option for the storage of hydrogen is the reversible hydrogenation of an aromatic substance, a so‐called liquid organic hydrogen carrier. For hydrogen release, it is desirable to find substances with low enthalpies of reaction for dehydrogenation. It has been demonstrated that substitution, e.g., with methyl groups, on the ring can have a positive effect in this regard. In this study, thermochemical properties of methoxy‐substituted pyridines and quinolines and their respective hydrogenated counterparts have been analyzed from a thermodynamic point of view. Combustion calorimetry has been utilized to measure the enthalpy of formation and the transpiration method for determining the vapor pressure. Additionally, high‐level quantum‐chemical approaches have been applied to obtain caloric data in the gas phase, which provide a basis for comparison and evaluation of the experimental data. The results reveal two main effects of methoxy substitution. First, oxygenated substituents like methoxy groups have stronger effect on the Gibbs energy of reaction and thus the temperature needed thermodynamically for hydrogen release than methyl groups. Second, the effect is highly depending on the position of the substitution on the ring. Particularly methoxy groups close to a N heteroatom can have a significant positive effect, which might enable hydrogen release at equilibrium temperatures more than 50 K lower than for their unsubstituted analogue.

Piperidinium surfactants functionalized with carbamate fragment: Aggregation, antimicrobial activity and cytotoxicity

The biomimetic nature of supramolecular systems, the structural similarity of synthetic surfactants to biomolecules (lipids, proteins), provide them with high membranotropy, the ability to overcome biological barriers, and affinity towards biosubstances. Despite rather high toxicity cationic surfactants are of importance as antimicrobial agents, gene nanocarriers and mitochondria targeted ligands. To minimize this limitation, cationic amphiphilic matrix undergoes modification with various functional groups. In this work, new piperidinium cationic surfactants containing one or two carbamate fragments were prepared; their aggregation behavior was systematically studied by tensiometery, spectrophotometry and fluorimetry. The presence of a carbamate fragment leads to a 2–3-fold decrease in critical micelle concentration and to a significant increase in solubilization capacity compared to unsubstituted analogue. Evaluation of the antimicrobial effect showed that all compounds exhibit high bactericidal and fungicidal activity against a wide range of pathogenic microorganisms, including their resistant forms. Importantly, the introducing carbamate moiety allows of decreasing hemolytic activity of cationic surfactants. The data obtained make it possible to recommend carbamate piperidinium surfactants as effective biocompatible and biodegradable nanocontainers for hydrophobic probes with high antimicrobial effect and moderate hemolytic activity.

Modulatory spin-flip of triplet excitons via diversiform electron-donating units for MR-TADF emitters towards solution-processed narrowband OLEDs.

Multiple resonance thermally activated delayed fluorescence (MR-TADF) molecules are emerging as promising candidates for high-resolution organic light-emitting diode (OLED) displays, but MR-TADF emitters always suffer from an unsatisfactory rate constant of reverse intersystem crossing (k RISC) due to inherently low spin orbital coupling strength between excited singlet and triplet states. Herein, we systematically investigate the long-range charge transfer (LRCT) and heavy-atom effects on modulating the excited state natures and energy levels via integrating diversiform electron-donating units with the MR skeleton. Compared with unsubstituted analogues, newly designed MR-TADF emitters exhibit significantly boosted k RISC values and close-to-unity photoluminescence quantum yield especially for tBuCzBN-PXZ (2.5 × 105 s-1) and tBuCzBN-Ph-PSeZ (2.1 × 105 s-1). Leveraging these exceptional properties, the maximum external quantum efficiency values of tBuCzBN-PXZ- and tBuCzBN-Ph-PSeZ-based solution-processed OLEDs can reach 21.3% and 19.4%, which are in the first tier of reported solution-processed MR-TADF binary OLEDs without employing additional sensitizers. This study provides a framework for modulating photoelectrical properties of MR-TADF emitters through fastidiously regulating LRCT and heavy-atom effects.

Substituent and Solvent Effects on the Spectral Properties of 3-Substituted Derivatives of 4-Hydroxycoumarin

Solvent and substitution effects on the UV/Vis spectroscopic and fluorescence behaviour of seven synthesized 3-substituted 4-hydroxycoumarin derivatives were tested. The tested compounds were dissolved in ethyl acetate, acetonitrile, and dimethyl sulfoxide. Absorption and emission spectra were recorded in the range of 200–800 nm. All tested 4-hydroxycoumarin derivatives showed good absorption in a wide range of 200–550 nm, depending on the properties of the substituents on the benzene ring of the cinnamoyl moiety and the type of solvent. In comparison to the unsubstituted analogue, compounds with an electron-donating group exhibited bathochromically shifted UV/Vis absorption and emission spectra. The highest fluorescence quantum yield was observed for compounds with dimethylamino and acetamido groups as substituents at the benzene ring. Considering that both substitution and solvent affect the absorption and emission spectra of the tested compounds, it can be concluded that judiciously selecting these parameters can improve their absorption and fluorescence properties, making them suitable for various analytical uses.

7-Guanidinyl Coumarins: Synthesis, Photophysical Properties, and Application to Exploit the Pd-Catalyzed Release of Guanidines.

Molecular manipulation of guanidino-containing biomolecules in a cellular environment is fundamental to exploiting protein function and drug release, but currently, there is a lack of suitable methods for reaction screening and monitoring. To exploit the potential of the fluorescent method in this respect, herein, we evaluated a novel array of 7-guanidinyl coumarins by incorporating different substituted guanidino moieties into a coumarin scaffold. These compounds were prepared by guanidinylation reagent S-methylisothiourea or TFA-protected pyrazole-carboxamidine. Examination of their photophysical properties revealed that the fluorescence emission of alkyloxycarbonyl-substituted guanidinyl coumarin was significantly enhanced as compared with the unsubstituted analogue. This dramatic fluorescence difference enabled preliminary exploitation of the Pd-catalyzed release of allyloxycarbonyl (Alloc)-caged guanidinyl coumarin-6 in living cells.

Reactivity of electrophilic cyclopropanes.

Cyclopropanes that carry an electron-accepting group react as electrophiles in polar, ring-opening reactions. Analogous reactions at cyclopropanes with additional C2 substituents allow one to access difunctionalized products. Consequently, functionalized cyclopropanes are frequently used building blocks in organic synthesis. The polarization of the C1-C2 bond in 1-acceptor-2-donor-substituted cyclopropanes not only favorably enhances reactivity toward nucleophiles but also directs the nucleophilic attack toward the already substituted C2 position. Monitoring the kinetics of non-catalytic ring-opening reactions with a series of thiophenolates and other strong nucleophiles, such as azide ions, in DMSO provided the inherent SN2 reactivity of electrophilic cyclopropanes. The experimentally determined second-order rate constants k 2 for cyclopropane ring-opening reactions were then compared to those of related Michael additions. Interestingly, cyclopropanes with aryl substituents at the C2 position reacted faster than their unsubstituted analogues. Variation of the electronic properties of the aryl groups at C2 gave rise to parabolic Hammett relationships.

Dyeing to Carry Charge: Commercial Phthalocyanine Dyes as Charge Carriers for Redox Flow Battery Applications

The development of inexpensive charge carriers with long-term stability is critical to increase the economic viability of redox flow batteries (RFBs). Herein, we compare the performance metrics of a series of synthesized or commercially available inexpensive phthalocyanine metal (PcM) charge carriers with varying metal- or ligand-based substitution patterns. All systems were charged–discharged as slurries in conjunction with a conductive heterogeneous carbon source, Ketjenblack (KB). The synthesized, peripherally substituted 1,4,8,11,15,18,22,25-octaethoxyphthalocyanine (EtOPc) metal complexes, OEtPcVO and OEtPcNi, were cycled with KB, and their performance metrics were compared to their commercially unsubstituted analogues, PcVO and PcNi. No significant advantages were found in using the synthesized versus commercial variants despite the increased solubility of the former. Expanding these electrochemical analyses to several commercial first-row variants (PcTiCl2, PcVO, PcMnCl, PcFe, PcCo, PcNi, and PcCu) as well as one heavy-metal analogue (PcPb) revealed that most of these were effective charge carriers for slurry-based PcM/KB RFB applications. Of these, PcCu proved to have the highest efficiencies, energy density (1.23 Wh/L), and stability (>99% capacity retention) of the series while also having the lowest cost by mass.

Reductive Elimination from Sterically Encumbered Ni-Polypyridine Complexes.

Herein we disclose the synthesis of sterically encumbered dialkylnickel(II) complexes bearing 2,9-dimethyl-1,10-phenanthroline ligands. A comparison with their unsubstituted analogues by both X-ray crystallography and theoretical calculations revealed significant distortions in their molecular structures. Eyring plots along with stoichiometric and photoexcitation studies revealed that sterically encumbered dialkylnickel(II) complexes enable facile C(sp3)–C(sp3) reductive elimination, thus offering an improved understanding of Ni catalysis.

Novel Ethylene Glycol Substituted Benzoxadiazole and Benzothiadiazole as Anolytes for Nonaqueous Organic Redox Flow Batteries

AbstractThe design of new organic materials for redox‐flow batteries is an actively developing topic in the field of energy storage. Herein, two novel redox‐active organic molecules were presented, based on benzoxadiazole and benzothiadiazole cores bearing ethylene glycol substituents, which were first synthesized and evaluated as anolytes in nonaqueous all organic redox flow batteries. These two molecules were compared with their unsubstituted analogs in terms of electrochemistry, solubility and RFB cycling behavior. Substituted benzoxadiazole and benzothiadiazole possess low redox potentials near −2.1 V vs. Fc/Fc+, increased solubility in organic solvents, reduced permeability through the membrane and higher stability under charge‐discharge cycling in laboratory RFB cells than unsubstituted counterparts.

Design, Molecular Docking, Synthesis, Characterization and Biological Activities of Novel Thiazole Derivatives

Aim: The study aims to design and synthesize novel thiazole derivatives as potent antitubercular agents with minimal side effects. Background: The emergence and rapid spread of multi-drug resistant infectious microbial flora embracing a variety of bacterial as well as mycobacterium strains are causing a threat to public health worldwide. Objective: Owing to the importance, we designed compounds with thiazole functionality coupled with Schiff base and thiosemicarbazide, predicted the molecular properties and antitubercular potency of designed compounds by the in-silico method, and synthesized fifteen novel thiazole analogs, characterized and tested in vivo antitubercular, antibacterial and antioxidant potencies. Methods: Molinspiration online tool was used to predict the molecular properties and molecular docking was used to predict the antitubercular potency. FT-IR, 1H-NMR, 13C-NMR, Mass spectroscopy and bases of elemental analysis are employed to confirm the structure of compounds. 10-Fold serial dilution method, agar streak dilution test and DPPH radical scavenging methods are used to estimate antitubercular, antibacterial and antioxidant potency of title analogs, respectively. Results: Multi-step synthesis was used to synthesize a variety of novel thiazole derivatives coupled with Schiff base and thiosemicarbazide. Synthesized title compounds displayed a varying degree of antitubercular, antibacterial and antioxidant activities (mild to good). The title compounds possessing deactivating group exhibited superior activities than activating group, while unsubstituted analogs displayed intermediate activities. In addition, para-substituted analogs showed slightly higher activity than the corresponding meta substituted analogs. Conclusion: Among fifteen tested title compounds, the potent compound of this series was found to be 1- (4-nitrobenzylidene)-4-(4-(4-methoxyphenyl)thiazol-2-yl)thiosemicarbazide (BTS14), which might be extended as a novel class of antitubercular and antibacterial agents.

Impact of bPNA Backbone Structural Constraints and Composition on Triplex Hybridization with DNA.

We report herein a study on the impact of bifacial peptide nucleic acid (bPNA) amino acid composition and backbone modification on DNA binding. A series of bPNA backbone variants with identical net charge were synthesized to display either 4 or 6 melamine (M) bases. These bases form thymine-melamine-thymine (TMT) base-triples, resulting in triplex hybrid stem structures with T-rich DNAs. Analyses of 6 M bPNA-DNA hybrids suggested that hybrid stability was linked to amino acid secondary structure propensities, prompting a more detailed study in shorter 4 M bPNAs. We synthesized 4 M bPNAs predisposed to adopt helical secondary structure via helix-turn nucleation in 7-residue bPNAs using double-click covalent stapling. Generally, hybrid stability improved upon stapling, but amino acid composition had a more significant effect. We also pursued an alternative strategy for bPNA structural preorganization by incorporation of residues with strong backbone amide conformational preferences such as 4R- and 4S-fluoroprolines. Notably, these derivatives exhibited an additional improvement in hybrid stability beyond both unsubstituted proline bPNA analogues and the helically patterned bPNAs. Overall, these findings demonstrate the tunability of bPNA-DNA hybrid stability through bPNA backbone structural propensities and amino acid composition.

Synthesis, Optical and Electrochemical Properties of Isomeric Dibenzophenanthroline Derivatives

AbstractAcid‐catalysed Friedländer cyclization of 2‐aminobenzophenones with 1,2‐, 1,3‐, and 1,4‐cyclohexadiones, followed by aromatization, has been used to prepare dibenzophenanthrolines (DBPs) containing 1,10‐, 1,7‐ and 4,7‐phenanthroline units, whose optoelectronic properties have been compared. The LUMO energies for all isomers were similar but the 4,7‐isomers possessed significantly higher HOMOs than the other isomers, resulting in them having smaller HOMO‐LUMO energy gaps. Compared with 1,10‐DBP isomers, the emission of 1,7‐DBPs is strongly quenched due to efficient charge transfer. The 4,7‐DBP isomers show strongly enhanced photoluminescence due to excimer formation but appear to be less photostable due to their higher HOMO levels. Bis(phenylethynyl)‐substituted derivatives demonstrated improved solubility and stronger luminescence properties than their unsubstituted analogues.

Cover Feature: Inherent Reactivity of Spiro‐Activated Electrophilic Cyclopropanes (Chem. Eur. J. 64/2021)

The kinetics of ring-opening reactions with thiophenolates in DMSO were monitored to assess the inherent SN2 reactivity of electrophilic cyclopropanes. Phenyl-substituted cyclopropanes reacted faster than their unsubstituted analogues. Variation in the electronic properties of substituents at the phenyl groups of the indandione-derived cyclopropanes gave rise to parabolic Hammett relationships, which revealed variable electrophile-dependent effects on the stabilization of the transition states. More information can be found in the Full Paper by A. R. Ofial et al. (DOI: 10.1002/chem.202103027). Artwork by A.S.

Inherent Reactivity of Spiro-Activated Electrophilic Cyclopropanes.

The kinetics of the ring‐opening reactions of thiophenolates with geminal bis(acceptor)‐substituted cyclopropanes in DMSO at 20 °C was monitored by photometric methods. The determined second‐order rate constants of the SN2 reactions followed linear relationships with Mayr nucleophilicity parameters (N/s N) and Brønsted basicities (pK aH) of the thiophenolates as well as with Hammett substituent parameters (σ) for groups attached to the thiophenolates. Phenyl‐substituted cyclopropanes reacted by up to a factor of 15 faster than their unsubstituted analogues, in accord with the known activating effect of adjacent π‐systems in SN2 reactions. Variation of the electronic properties of substituents at the phenyl groups of the cyclopropanes gave rise to parabolic Hammett relationships. Thus, the inherent SN2 reactivity of electrophilic cyclopropanes is activated by electron‐rich π‐systems because of the more advanced C1−C2 bond polarization in the transition state. On the other hand, electron‐poor π‐systems also lower the energetic barriers for the attack of anionic nucleophiles owing to attractive electrostatic interactions.

Induced Nematic Phase of New Synthesized Laterally Fluorinated Azo/Ester Derivatives.

A new series of laterally fluorinated mesomorphic compounds, namely 2-fluoro-4-((4-(alkyloxy)phenyl)diazenyl)phenyl 4-substitutedbenzoate (Inx) were prepared and evaluated for their mesophase behavior. The synthesized series constitutes five members that possess different terminally attached polar groups (X). Their molecular structures were confirmed by elemental analyses and both FT-IR and NMR spectroscopy. Examination of the prepared derivatives was conducted via experimental and theoretical tools. Mesomorphic investigations were carried by polarized optical microscopy (POM) and differential scanning calorimetry (DSC). DSC and POM measurements indicated that except for the un-substituted analogue, all other derivatives were purely nematogenic, possessing their nematic (N) mesophase enantiotropically. This is to say that insertions of terminal polar substituents on their mesogenic structures induced the N phase. In addition, the location of lateral and terminal polar moieties played a considerable role in achieving good thermal N stability. Computational calculations were investigated to determine the deduced optimized molecular structures. Theoretical data indicated that both size and polarity of the terminal substituent (X) have essential impact on the thermal parameters and optical properties of possible geometries.

Structure-Function Relationships of Novel Benzimidazole-Based Inhibitors of the Isoprenoid Biosynthetic Pathway in Myeloma Cells

Malignant plasma cells are characterized by the production of monoclonal protein (MP). Our work has demonstrated that disrupting intracellular MP trafficking by targeting the geranylgeranylation of Rab GTPases results in endoplasmic reticulum stress, induction of the unfolded protein response pathway and apoptosis of myeloma cells. Rab proteins are geranylgeranylated by the enzyme geranylgeranyl transferase II (GGTase II) which uses geranylgeranyl diphosphate as the isoprenoid substrate. We have pursued the development of specific GGTase II and geranylgeranyl diphosphate synthase (GGDPS) inhibitors as potential anti-myeloma agents. A family of compounds incorporating a benzimidazole heterocycle and either a carboxyphosphonate or bisphosphonate was prepared by modification of the appropriate heterocycles. The core benzimidazole phosphonate structure was modified with substituents at either the alpha-carbon position or at the 5 and 6 positions on the benzimidazole (Figure). These compounds were subjected to in vitro enzyme assays for GGTase II and the related prenyltransferases farnesyl transferase (FTase) and GGTase I as well as the synthases farnesyl diphosphate synthase (FDPS) and GGDPS. Cellular disruption of protein prenylation was assessed via immunoblot analysis for Ras (a representative farnesylated protein) and for unmodified Rap1a (a representative geranylgeranylated protein) in human myeloma cells (RPMI-8226, MM.1S). The ability of the novel compounds to disrupt MP trafficking was determined by measuring changes in intracellular lambda light chain levels via ELISA. Confirmation of disruption of Rab geranylgeranylation was achieved by Triton X-114 lysis to obtain detergent (membrane) fractions which were subjected to Rab6 (a representative Rab protein) immunoblot analysis. These studies demonstrated that the nature of the phosphonate head group has a profound impact on enzyme specificity: the carboxyphosphonates have specific activity as GGTase II inhibitors while the bisphosphonate analogues have specific activity as FDPS inhibitors with no cross-reactivity against any of the other tested enzymes. The most potent GGTase II and FDPS inhibitors were the unsubstituted analogues. The carboxyphosphonate 1 was found to have an IC50 of 230 μM against GGTase II and cellular activity starting at 2.5 mM. This represents a two-fold improvement in potency compared with the known GGTase II inhibitor 3-PEHPC. The bisphosphonate 5 has an IC50 of 24 nM against FDPS and cellular activity at ≥ 50 μM. The addition of a methyl group at the alpha-carbon position abrogated the activity of the carboxyphosphonate (2) as a GGTase II inhibitor and the activity of the bisphosphonate (6) as a FDPS inhibitor. The addition of substituents at the 5 and 6 positions (compounds 3, 4, 7 and 8)did not improve potency compared with the parent compounds. Co-incubation with low concentrations of the HMG-CoA reductase inhibitor lovastatin (0.1-1 μM), concentrations which on their own are not sufficient to disrupt protein prenylation, potentiated the cellular activity of the lead GGTase II and FDPS inhibitors. In conclusion, these benzimidazole phosphonates represent novel classes of GGTase II and FDPS inhibitors. These studies highlight the importance of the identity of the phosphonate head-group in dictating enzyme specificity. Further studies are underway to prepare additional benzimidazole analogues in order to improve their potency, advance the understanding of the structure-function relationship, and assess the potential of these compounds as anti-myeloma agents. [Display omitted] DisclosuresWiemer:Terpenoid Therapeutics, Inc: Other: Founder. Holstein:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy.