Ring Side Chain Research Articles

The stability of columns comprising alternating triphenylene and hexaphenyltriphenylene molecules: variations in the structure of the hexaphenyltriphenylene component

Previous investigations of complementary polytopic interaction (CPI) columnar mesophases, in which the columns are built up of alternating hexaalkoxytriphenylene (HAT) and hexaphenyltriphenylene (PTP) molecules, concentrated mainly on the effect of variations in the structure of the HAT component. This investigation is concerned with the effect of variations in the structure of the PTP component and, in particular, variations in the position of an alkoxy side chain in the phenyl ring. Stable columnar mesophases are obtained when a hexyloxy substituent is placed in the meta‐ or para‐position but not in the ortho‐position. In the case of the meta‐ and para‐substituted systems, the two‐component CPI columnar phases are stable over a considerably larger temperature range than the one‐component HAT systems. The evidence suggests that unfavourable PTP/PTP stacking is as much a driving force for the formation of these mixed stacks as is favourable PTP/HAT stacking, but both need to be explained in terms of the sum of atomically dispersed van der Waals and coulombic interactions. On cooling from the isotropic into the Colh phase, the columnar phase based on a 1:1 mixture of hexakis(hexyloxy)tripenylene and the meta‐hexyloxy‐substituted PTP gives an unusual texture consisting of ‘viking‐axe’‐shaped structures.

The Substrate Radical of Escherichia coli Oxygen-independent Coproporphyrinogen III Oxidase HemN

During porphyrin biosynthesis the oxygen-independent coproporphyrinogen III oxidase (HemN) catalyzes the oxidative decarboxylation of the propionate side chains of rings A and B of coproporphyrinogen III to form protoporphyrinogen IX. The enzyme utilizes a 5'-deoxyadenosyl radical to initiate the decarboxylation reaction, and it has been proposed that this occurs by stereo-specific abstraction of the pro-S-hydrogen atom at the beta-position of the propionate side chains leading to a substrate radical. Here we provide EPR-spectroscopic evidence for intermediacy of the latter radical by observation of an organic radical EPR signal in reduced HemN upon addition of S-adenosyl-L-methionine and the substrate coproporphyrinogen III. This signal (g(av) = 2.0029) shows a complex pattern of well resolved hyperfine splittings from at least five different hydrogen atoms. The radical was characterized using regiospecifically labeled (deuterium or 15N) coproporphyrinogen III molecules. They had been generated from a multienzyme mixture and served as efficient substrates. Reaction of HemN with coproporphyrinogen III, perdeuterated except for the methyl groups, led to the complete loss of resolved proton hyperfine splittings. Substrates in which the hydrogens at both alpha- and beta-positions, or only at the beta-positions of the propionate side chains, or those of the methylene bridges, were deuterated showed that there is coupling with hydrogens at the alpha-, beta-, and methylene bridge positions. Deuterium or 15N labeling of the pyrrole nitrogens without labeling the side chains only led to a slight sharpening of the radical signal. Together, these observations clearly identified the radical signal as substrate-derived and indicated that, upon abstraction of the pro-S-hydrogen atom at the beta-position of the propionate side chain by the 5'-deoxyadenosyl radical, a comparatively stable delocalized substrate radical intermediate is formed in the absence of electron acceptors. The observed hyperfine constants and g values show that this coproporphyrinogenyl radical is allylic and encompasses carbon atoms 3', 3, and 4.

A Fragment‐weighted Key‐based Similarity Measure for Use in Structural Clustering and Virtual Screening

AbstractA new similarity measure and structural clustering method has been developed in which each structure is fragmented into ring systems, linkers, and side chains, and where the similarity between structures forms a weighted sum of the similarities between each set of fragments. We have applied the MACCS keys as molecular descriptors and identified a number of ways in which to improve the use of these keys for structural clustering and virtual screening. The method has been optimized to reproduce scaffold‐biased clustering commonly used in medicinal chemistry.

Conformational flexibility of mammalian cytochrome P450 2B4 in binding imidazole inhibitors of different ring chemistry and side chains

Recent x-ray structures of cytochrome P450 2B4 (CYP2B4) reveal an open form that undergoes a large-scale structural transition to a closed form upon 4-(4-chlorophenyl)imidazole (4-CPI) binding. Here we report for the first time using isothermal titration calorimetry (ITC) and spectroscopic titrations the conformational flexibility of CYP2B4 in solution upon binding six different inhibitors:4-CPI, 1-benzylimidazole, 4-phenylimidazole, 1-(4-chlorophenyl)imidazole, 1-phenylimidazole and 1-(2-(benzyloxy)ethyl)imidazole (BEI). All the inhibitors induce type-II spectral changes. Calorimetric titrations using monomeric enzyme yielded 1:1 binding stoichiometry with the associated KD values ranging from 0.2 μM to 4.8 μM and changes in enthalpy from −6.5 to −8.8 kcal mol−1. The largest difference in entropy (+5.9 vs. −4.1 cal mol−1K−1) and heat capacity change (−604 vs. −331 cal mol−1K−1) was observed between 4-CPI and BEI. Interaction of all six inhibitors was enthalpically driven and hydrophobic, and only 4-CPI induces large conformational change in the enzyme. Accessibility to acrylamide of the only tryptophan (Trp121) and molecular modeling studies complement these findings. The thermodynamic signature obtained from ITC can be an excellent resource for minimizing deleterious P450 interactions in rational drug design and for picking compounds for structural analysis of P450 enzymes. NCAA Grant MCB050038N (BKM), NIH Grant ES03619, and Center grant ES06676 (J.R.H.).

Conformational Flexibility of Mammalian Cytochrome P450 2B4 in Binding Imidazole Inhibitors with Different Ring Chemistry and Side Chains: SOLUTION THERMODYNAMICS AND MOLECULAR MODELING

Recent x-ray structures of cytochrome P450 2B4 (CYP2B4) reveal an open form that undergoes a large-scale structural transition to a closed form upon binding to 4-(4-chlorophenyl)imidazole (4-CPI). Here, we report for the first time a complete solution thermodynamic study using isothermal titration calorimetry supported by spectroscopic studies to elucidate the conformational flexibility of CYP2B4 in binding imidazole inhibitors with different ring chemistry and side chains: 4-CPI, 1-benzylimidazole (1-BI), 1-CPI, 4-phenylimidazole (4-PI), 1-(2-(benzyloxy)ethyl)imidazole (BEI), and 1-PI. Each of the inhibitors induced type II spectral changes, and IC50 values for enzyme inhibition ranged from 0.1 to 2.4 microM, following the order 1-BI < 4-CPI < 1-CPI < 4-PI < BEI < 1-PI. Calorimetric titrations using monomeric enzyme yielded a 1:1 binding stoichiometry, with the associated KD values ranging from 0.3 to 4.8 microM and following the same rank order as the IC50 values. Changes in enthalpy at 25 degrees C ranged from -6.5 to -8.8 kcal mol(-1). The largest difference in binding entropy (+5.9 versus -4.1 cal mol(-1) K(-1)) was observed between 4-CPI and BEI, respectively, with a 2-fold difference in heat capacity changes (-604 versus -331 cal mol(-1) K(-1)), which is inferred to result from the reduction of apolar surface area of the enzyme ensuing from a conformational change upon 4-CPI binding. Accessibility to acrylamide of the only tryptophan (Trp121), which is located in helix C, was greatly decreased only in protein bound to 4-CPI. Steric restrictions hindered the perfect docking of only BEI to the closed conformation of the enzyme. The thermodynamic signature obtained for structurally similar inhibitors suggests remarkable plasticity of CYP2B4.

Structure−Activity Relationship of Cyclic Nitroxides as SOD Mimics and Scavengers of Nitrogen Dioxide and Carbonate Radicals

Synthetic nitroxide antioxidants attenuate oxidative damage in various experimental models. Their protective effect reportedly depends on ring size and ring substituents and is greater for nitroxides having lower oxidation potential. The present study focuses on the kinetics and mechanisms of the reactions of piperidine, pyrrolidine and oxazolidine nitroxides with HO2*/O2*-, *NO2 and CO3*- radicals, which are key intermediates in many inflammatory and degenerative diseases. It is demonstrated that nitroxides are the most efficient scavengers of *NO2 at physiological pH (k = (3-9) x 10(8) M(-1) s(-1)) and among the most effective metal-independent scavengers of CO3*- radicals (k = (2 - 6) x 10(8) M(-1) s(-1)). Their reactivity toward HO2*, though not toward *NO2 and CO3*-, depends on the nature of the ring side-chain and particularly on the ring-size. All nitroxide derivatives react slowly with O2*- and are relatively inefficient SOD mimics at physiological pH. Even piperidine nitroxides, having the highest SOD-like activity, demonstrate a catalytic activity of about 1000-fold lower than that of native SOD at pH 7.4. The present results do not indicate any correlation between the kinetics of HO2*/O2*-, *NO2 and CO3*- removal by nitroxides and their protective activity against biological oxidative stress and emphasize the importance of target-oriented nitroxides, i.e., interaction between the biological target and specific nitroxides.

Ring-Toss: Capping highly exposed tyrosyl or tryptophyl residues in proteins with β-cyclodextrin

We have used UV difference spectroscopy and fluorescence spectroscopy to study the perturbation by β-cyclodextrin of tyrosyl or tryptophyl residues located at each of the 10 variable consensus contact positions in the third domain of turkey ovomucoid. The goal was to monitor the accessibility of the side chain rings of these residues when located at these positions. The results indicated that the tyrosyl or tryptophyl rings are most highly exposed when located in the P 1 position followed by the P 4 position. It was possible to determine the association constants for β-cyclodextrin binding at these positions. When located at the P 2, P 5, P 6 and P 3′ positions, the rings of the tyrosyl or tryptophyl residues were exposed but less so than at the P 1 or P 4 positions. By contrast, when located at the P 1′, P 2′, P 14 ′ and P 18 ′ positions, the tyrosyl or tryptophyl residues were insufficiently exposed to be perturbed by β-cyclodextrin, although they reacted positively to dimethyl sulfoxide solvent perturbation. These findings indicate that β-cyclodextrin perturbation provides a convenient way to detect highly exposed tyrosyls or tryptophyls in proteins. Furthermore, we evaluated the ability of β-cyclodextrin to inhibit the interaction of turkey ovomucoid third domain variants with different P 1 residues. The results showed that the presence of β-cyclodextrin had little effect on the association constant when the P 1 residue was a glycyl residue, but greatly decreased the association constant when the P 1 residue was a tyrosyl or tryptophyl residue. Thus, β-cyclodextrin may be used to selectively modulate the interaction between proteinase inhibitors and their cognate enzymes.

Water-Assisted Oxo Mechanism for Heme Metabolism

A mechanism of heme metabolism by heme oxygenase (HO) is discussed from B3LYP density functional theory calculations. The concerted OH group attack to the alpha-carbon by the iron-hydroperoxo species is investigated using a model with full protoporphyrin IX to confirm our previous conclusion that this species does not have sufficient oxidizing power for heme oxidation (J. Am. Chem. Soc. 2004, 126, 3672). Calculated activation energies and structures of the intermediates and transition state for this process remain unchanged from those for a small model with porphine in the previous study, which shows that the inclusion of the side chain of the porphyrin ring is not essential in describing the OH group transfer. The activation barrier for a direct oxo attack to the alpha-carbon by an iron-oxo model is calculated to be 49.8 kcal/mol, the barrier height of which looks very high for the enzymatic reaction under physiological conditions. This large activation energy is due to a highly bent porphyrin structure in the transition state. However, a bridging water molecule plays an important role in reducing the porphyrin distortion in the transition state, resulting in a remarkable decrease of the activation barrier to 13.9 kcal/mol. A whole-enzyme model with about 4000 atoms is constructed to elucidate functions of the protein environment in this enzymatic reaction using QM/MM calculations. The key water molecule is fixed in the protein environment to ensure the low-barrier and regioselective heme oxidation. A water-assisted oxo mechanism of heme oxidation by heme oxygenase is proposed from these calculational results.

X‐ray reflectivity study of cyclic peptide monolayers at the air‐water interface

AbstractThe dynamic and living characteristics of monolayers at the air‐water interface of a cyclohexapeptide (C6G) and a cyclooctapeptide (C8G), both composed of glutamic acid and 3‐aminobenzoic acid subunits in an alternating sequence, were investigated using the Langmuir balance technique, Brewster angle microscopy (BAM), and X‐ray reflectivity (XR). An alanine‐containing cyclohexapeptide (C6A) was included in this study for comparison. All three cyclopeptides preferentially adopt an orientation parallel to the subphase at low surface pressure. Continuous compression then causes the molecules to flip to a perpendicular state, thus minimizing their molecular area. In contrast to C8G and C6A, a pronounced hysteresis observed during the compression‐expansion cycle of C6G indicates that strong intermolecular interactions between the cyclopeptide rings occur in the monolayers of this peptide. This result is supported by BAM measurements that show the formation of crystallite structures for C6G at high surface pressures, whereas no structures were observed for C8G and C6A. These results indicate that C6G is able to self‐assemble upon surface compression, an ability that is obviously critically dependent on the correct ring size and composition of the peptide. The presence of hydrogen bond acceptors in the side chains of C6G suggests that the structural stabilization of the monolayer is due to H‐bonding, possibly between ring NH groups and side chain CO groups. Our in situ study thus provides a detailed understanding of the molecular dynamics and uninterrupted interfacial behavior of the three peptides in a real‐time frame.

Hetero-association of anticancer antibiotics in aqueous solution: NMR and molecular mechanics analysis

In order to investigate the effect on combinations of aromatic antibiotics used in chemotherapy, the hetero-association of the antitumour antibiotics actinomycin D (AMD) with daunomycin (DAU) or novatrone (NOV) has been studied by the methods of 1D- and 2D 500 MHz 1H-NMR spectroscopy and molecular mechanics calculations. The experimental concentration and temperature dependences of the proton chemical shifts of mixtures of the aromatic drugs have been analyzed in terms of a modified statistical–thermodynamical model of hetero-association to give the equilibrium reaction constants, the thermodynamical parameters (Δ H, Δ S) of hetero-association of AMD with DAU or NOV and the limiting values of proton chemical shifts of the molecules in the hetero-complexes. The most favorable averaged structures of the 1:1 DAU–AMD and NOV-AMD hetero-association complexes have been determined using both the limiting values of proton chemical shifts of the molecules and molecular mechanics methods (X-PLOR software). The results show that intermolecular complexes between DAU–AMD and NOV–AMD are mainly stabilized by stacking interactions of the aromatic chromophores, although the DAU–AMD hetero-complex has additional stabilization, which may be explained by an intermolecular hydrogen bond between a carbonyl group of ring C of DAU and the NH group of D–Val of the pentapeptide side chain ring of AMD. The relative content of each type of molecular complex in the mixed solution has been calculated at different values of the ratio ( r) of the initial concentrations of DAU and AMD. It is found that the contributions of hetero-complexes to the general equilibrium in solution are predominant at quite different values of r, viz. at r > 12 for AMD with NOV and at r > 2 for AMD with DAU, compared to r > 0.3 for the DAU–NOV system observed previously. It is concluded that anticancer drugs have quite different affinities for formation of hetero-complexes with other aromatic antibiotics in aqueous solution, which may need to be taken into consideration for their use in combination chemotherapy.

Construction of Building‐Blocks for Polyether Synthesis Using Sequential Catalytic Ring‐Closing Enyne and Cross Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and evaluation of new ω-borono-α-amino acids as rat liver arginase inhibitors

Recent studies have demonstrated that arginase plays important roles in pathologies such as asthma or erectile dysfunctions. We have synthesized new ω-borono-α-amino acids that are analogues of the previously known arginase inhibitors S-(2-boronoethyl)- l-cysteine (BEC) and 2-amino-6-boronohexanoic acid (ABH) and evaluated them as inhibitors of purified rat liver arginase (RLA). In addition to the distance between the B(OH) 2 and the α-amino acid functions, the position of the sulfur atom in the side chain also appears as a key determinant for the interaction with the active site of RLA. Furthermore, substitution of the alkyl side chain of BEC by methyl groups and conformational restriction of ABH by incorporation of its side chain in a phenyl ring led to inactive compounds. These results suggest that subtle interactions govern the affinity of inhibitors for the active site of RLA.

Synthesis and evaluation of the permeability transition inhibitory characteristics of paramagnetic and diamagnetic amiodarone derivatives

Several amiodarone analogues were synthesized varying the 2-substituent on the benzofuran ring and diethylaminoethyl side chain of phenolether by introducing 2,2,5,5-tetramethyl-2,5-dihydro-1 H-pyrrole and 1,2,5,6-tetrahydropyridine nitroxides or their amino or hydroxylamino precursors. The new compounds were screened on isolated mitochondria and perfused heart and their toxicity was evaluated on WRL-68 liver cells and H9C2 cardiomyocytes. Most of the newly synthesized derivatives exerted uncoupling effect on the mitochondrial oxidative phosphorilation at higher concentrations, compared to amiodarone and one of the modified amiodarone analogues showed an effect similar to that of amiodarone on the mitochondrial permeability transition and on restoring of mitochondrial high-energy phosphate metabolites in perfused hearts. This amiodarone analogue can be new leading compound among the experimental amiodarone analogues with the same or enhanced efficiency of amiodarone, but with less side effects.

Synthesis and in Vitro Antifolate Activity of Rotationally Restricted Aminopterin and Methotrexate Analogues

Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is prevented by a CH(2) bridge were synthesized and tested for in vitro antifolate activity. The K(i) of the AMT analogue (9) against human dihydrofolate reductase (DHFR) was 34 pM, whereas that of the MTX analogue (10) was 2100 pM. Both compounds were less potent than the parent drugs. However, although the difference between AMT and MTX was <2-fold, the difference between 9 and 10 was 62-fold, suggesting that the effect of N(10)-methyl substitution is amplified in the bridged compounds. The K(i) values of 9 and 10 as inhibitors of [(3)H]MTX influx into CCRF-CEM human leukemia cells via the reduced folate carrier (RFC) were 0.28 and 1.1 muM, respectively. The corresponding K(i) and K(t) values determined earlier for AMT and MTX were 5.4 and 4.7 muM, respectively. Thus, in contrast to its unfavorable effect on DHFR binding, the CH(2) bridge increased RFC binding. In a 72 h growth assay with CCRF-CEM cells, the IC(50) values of 9 and 10 were 5.1 and 140 nM, respectively, a 27-fold difference that was qualitatively consistent with the observed combination of weaker DHFR binding and stronger RFC binding. Although rotationally restricted inhibitors of other enzymes of folate pathway enzymes have been described previously, 9 and 10 are the first reported examples of DHFR inhibitors of this type.

Three‐Carbon Ring Expansion by Cyclopropane Insertion: Macrocyclic Musks from Readily Available C‐12 Starting Materials.

AbstractFor Abstract see ChemInform Abstract in Full Text.

ANALYSIS OF SUBSTRATE SPECIFICITIES AND TISSUE EXPRESSION OF RAT UDP-GLUCURONOSYLTRANSFERASES UGT1A7 AND UGT1A8

The UGT1 complex codes for a subfamily of homologous "1A7-like" UDP-glucuronosyltransferases (UGTs), including UGT1A7 and UGT1A8. Little information is available regarding either the substrate specificities or regulation of the UGT1A7-like forms from rats. We compared the activities and tissue expression of UGT1A7 and UGT1A8, which exhibit 77% identity in their amino terminal sequence. UGT1A7 shows broad specificity, catalyzing the glucuronidation of 31 of 40 randomly selected substrates (100 muM) at rates >0.1 nmol/mg/min. UGT1A7 substrates included both planar and nonplanar compounds, mono- and polycyclic aromatics, and compounds with bulky side chain ring substitutions. UGT1A8 exhibited a narrower substrate specificity that completely overlapped with UGT1A7. UGT1A8 was most active toward the 1-OH, 4-OH, 5-OH, 6-OH, 7-OH, 10-OH, 11-OH, and 12-OH derivatives of benzo[a]pyrene. Other effective UGT1A8 substrates (>0.1 nmol/mg/min) included 9-OH-benzo[a]pyrene, 1-naphthol, 4-methylumbelliferone, 7-hydroxycoumarin, chrysin, quercetin, 4-nitrophenol, and estriol. In general, substrates preferred by UGT1A8 were polyaromatic planar structures with nonbulky substituents and a superimposable 1-naphtho ring structure. Studies of the tissue expression of the UGT1A7 and 1A8 mRNAs using RNase protection analysis suggested that each is expressed in liver and kidney of control rats. A major difference is the higher expression of UGT1A7 mRNA in intestine. These studies suggest complementary functions of the UGT1A7 and UGT1A8 forms in xenobiotic metabolism. Further studies are necessary to determine whether their relative contributions change as a function of development, hormonal status, or exposure to inducing agents.

Chromatographic and Mass Spectral Studies on Isobaric and Isomeric Substances Related to 3,4-Methylenedioxymethamphetamine

A series of isobaric and isomeric molecules related to 3,4methylenedioxymethamphetamine (3,4-MDMA) are prepared and evaluated as potential mass spectral equivalents to this controlled substance. These compounds have the potential to produce a mass spectrum equivalent to 3,4-MDMA, thus making mass spectrometry a nonconclusive method for confirming the identity of any one of the substances. The various isomeric forms of the methoxymethylphenethylamines and the methoxymethcathinones have mass spectra essentially equivalent to 3,4-MDMA, but the ethoxy substituted phenethylamines show a unique fragment at m/z 107. Gas chromatographic separation on nonpolar stationary phases successfully resolved these compounds from 3,4-MDMA, however only a limited set of side chain regioisomers and ring substitution patterns are evaluated in this initial study.

Three-carbon ring expansion by cyclopropane insertion: macrocyclic musks from readily available C-12 starting materials.

A thermal three-carbon ring expansion based on side chain ring insertion of a cyclopropane moiety is described. Flash vacuum pyrolysis (FVP) of 1-cyclopropyl-cycloalk-3-enol derivatives leads to the three-carbon ring expanded enones with clean retention of double bond geometry. Substrates bearing methyl groups on the cyclopropane ring undergo regioselective bond cleavage, allowing for the systematic preparation of selectively substituted macrocyclic musks from low-priced C-12 starting compounds.

Enzymatic synthesis of new aromatic and aliphatic esters of flavonoids using Candida antarctica lipase as biocatalyst

Enzymatic acylation of rutin and esculin with aromatic, aliphatic and aryl-aliphatic acids using Candida antarctica lipase in tert amyl alcohol as solvent was investigated under low water content. Whatever the acyl donor used, the conversion yields and initial rates for esculin were higher than for rutin. For a given flavonoid, the performance of these reactions depended on the acyl donor structures. For aliphatic acids, conversion yields and initial rates of both flavonoids were respectively in the ranges of 68–90% and of 9.5×10−2–72×10−2 mmol l−1 h−1. For aromatic acids, the reaction occurred only with the aryl subgroup (cinnamic, hydrocinnamic, 3,4-dihydroxyhydrocinnamic and 4-hydroxyphenyl acetic acids) and was drastically influenced by the presence of side chain and substitution patterns of the aromatic ring. Except for hydrocinnamic acid (75%, 23.4×10−2 mmol l−1 h−1), with these acids the conversion yields and initial rates were lower and in the range of 10–45% and of 0.7×10−2 to 12.1×10−2 mmol l−1 h−1. Unsaturation of the side chain of the hydrocinnamic acid decreased the esculin conversion rate from 75 to 13% and initial rate from 23.4 to 1.76×10−2 mmol l−1 h−1. The presence of hydroxyl or nitro-groups on the aromatic ring of the aryl aliphatic acid also reduced conversion yields and initial rates. Even without a spacer, the non-phenolic ring acid (quinic acid) was reactive and lead to conversion yields of about 20 and 23% respectively for rutin and esculin.

Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum.

Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodium falciparum was recently described. Interestingly, some intermediates and final products biosynthesized by this pathway in mammals differ from those biosynthesized in P. falciparum. These facts prompted us to evaluate various terpenes, molecules with a similar chemical structure to the intermediates of the isoprenoids pathway, as potential antimalarial drugs. Different terpenes and S-farnesylthiosalicylic acid were tested on cultures of the intraerythrocytic stages of P. falciparum, and the 50% inhibitory concentrations for each one were found: farnesol, 64 microM; nerolidol, 760 nM; limonene, 1.22 mM; linalool, 0.28 mM; and S-farnesylthiosalicylic acid, 14 microM. All the terpenes tested inhibited dolichol biosynthesis in the trophozoite and schizont stages when [1-(n)-(3)H]farnesyl pyrophosphate triammonium salt ([(3)H]FPP) was used as precursor. Farnesol, nerolidol, and linalool showed stronger inhibitory activity on the biosynthesis of the isoprenic side chain of the benzoquinone ring of ubiquinones in the schizont stage. Treatment of schizont stages with S-farnesylthiosalicylic acid led to a decrease in intensity of the band corresponding a p21(ras) protein. The inhibitory effect of terpenes and S-farnesylthiosalicylic acid on the biosynthesis of both dolichol and the isoprenic side chain of ubiquinones and the isoprenylation of proteins in the intraerythrocytic stages of P. falciparum appears to be specific, because overall protein biosynthesis was not affected. Combinations of some terpenes or S-farnesylthiosalicylic acid tested in this work with other antimalarial drugs, like fosmidomycin, could be a new strategy for the treatment of malaria.