Carboxylic Acid Analogues Research Articles

Unusually large reactivity differences in the transformation of cyclopropane lactones to 1‐aminocyclopropane‐1‐phosphonic acids and their carboxylic acid analogues

AbstractStarting from a cyclopropane lactone 5, the synthesis of a 1‐aminocyclopropane‐1‐phosphonic acid derivative 11 is described. The considerable differences in the reactivity of the lactone ring opening in the case of a cyclopropane lactone substituted by a phosphonic acid ester 5 and their carboxylic acid ester analogue 2 toward ammonia or amines have been compared and interpreted by using the map of electrostatic potentials. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:90–96, 2001

Heterogeneous catalytic hydrogenation of olefinic substrates by poly-NAP

With our previously described poly-NAP, various olefinic substrates were reduced with selectivities comparable to those obtained by BINAP. For substrates which contained a methyl ester, the selectivities were higher than those observed for their carboxylic acid analogues.

Comparison of celecoxib metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit,the EM(extensive) and PM(poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.

Synthesis of [11C]2?-carbomethoxy-3?-(3?-iodo-4?-methyl, -ethyl and isopropyl phenyl)nortropane as potential radiotracers for examination of the serotonin transporter with positron emission tomography

Research on depression and anxiety disorders would benefit from the development of suitable radioligands for PET-imaging of the serotonin transporter. Three cocaine analogues, 2β-carbomethoxy-3β-(3′-iodo-4′-methyl, -ethyl and isopropyl phenyl)nortropane (LBT-14, EINT and LBT-44), were prepared in a three-step synthesis by 1-4 addition of the appropriate Grignard reagent to anhydroecgonine methyl ester as first step. Iodination of the phenyl ring was accomplished with a mixture of yellow mercuric oxide, perchloric acid and acetic acid followed by a solution of iodine in dichloromethane. N-desmethylation was performed by using 2,2,2-trichloroethylchloroformiate followed by treatment of zinc in acetic acid. Acidic hydrolysis of the ester functions gave the carboxylic acid analogues of LBT-14, EINT and LBT-44. The precursors were labelled with 11C using [11C]methyl iodide or [11C] methyl triflate in dimethyl formamide (DMF) and tetrabutyl ammonium hydroxide (TBAH) as base. [11C]LBT-14, [11C]EINT and [11C]LBT-44 were all examined in Cynomolgus monkey with PET. All three compounds entered the monkey brain to a high degree (5∽–10% of injected dose). There was a marked uptake of radioactivity in the thalamus and the brain stem, regions known to contain serotinin transporters. Pre-treatment with the selective serotonin transporter inhibitor citalopram had minor effect on the binding ratios, suggesting that none of the three examined radioligands are preferable to the previously examined non-iodinated 4′-isopropenyl analogue [11C]RTI-357 for the study of the serotonin reuptake system with PET. Copyright © 2000 John Wiley & Sons, Ltd.

PET examination of three potent cocaine derivatives as specific radioligands for the serotonin transporter

Several positron emission tomography (PET) radioligands based on the aryl tropane structure have been used for studies on monoamine reuptake sites. RTI-364, RTI-330, and RTI-357 (3-β-(4′- n-propyl-, 4′-iso-propyl-, and 4′-iso-propenyl-phenyl)nortropane-2-β-carboxylic acid methyl ester) are three recently synthesized cocaine analogues with higher affinity for the serotonin (5-HTT) than the dopamine transporter (DAT). Unlabelled RTI-364 and RTI-330 were prepared in a two-step synthesis. The key step was the addition of the appropriate propyl Grignard reagent to anhydroecgonine methyl ester. RTI-357 was prepared in a three-step synthesis with a palladium-catalyzed coupling reaction of β-CIT and isopropenylzinc bromide as key step. Hydrolysis of the ester functions gave the carboxylic acid analogues of RTI-364, RTI-330, and RTI-357, which were labelled with 11C using [ 11C]methyl iodide in dimethyl formamide (DMF) and tetrabutylammonium hydroxide (TBAH) as base. All three compounds entered the monkey brain in a high degree (∼5–10%). There was a low uptake of [ 11C]RTI-364 in serotonin-rich brain areas, whereas [ 11C]RTI-330 and [ 11C]RTI-357 showed a marked uptake of radioactivity in the thalamus and the brainstem, regions known to contain serotonin transporters. Transient equilibrium was reached at 15 and 40 min for [ 11C]RTI-330 and [ 11C]RTI-357, respectively. After pretreatment with citalopram, the ratio of radioactivity in the thalamus and the brainstem to the cerebellum were markedly reduced for [ 11C]RTI-357 but not for [ 11C]RTI-330. The results indicate that [ 11C]RTI-357 is a potential PET radioligand for quantitation of the serotonin reuptake site.

Mutagenesis study on human galanin receptor GalR1 reveals domains involved in ligand binding.

Many receptor mutants were generated and several NH2-terminally modified galanin analogs synthesized to define the regions of hGalR1 involved in galanin binding. Ligand binding properties and functionality of mutant receptors were evaluated. The His264Ala and Phe282Ala receptor mutants, although deficient in binding in the concentration range of galanin used, remained functional albeit at least 20-fold less efficient than the wild-type receptor in the inhibition of stimulated cAMP production. Hence, His264 and Phe282 of hGalR1 are directly involved in galanin binding. NH2-terminal carboxylic acid analogs of galanin (1-16) have a very low affinity for the wild-type receptor, but substantially increased affinity for the Glu271Lys-hGalR1, suggesting that the NH2-terminus of galanin binds to the receptor near the transmembrane (TM) VI. Based on these findings and computer-aided molecular modeling, we propose a binding site model for the hGalR1 receptor (possibly also for other galanin receptor subtypes): galanin binds with its NH2-terminus to the pocket between TM III and TM VI, Trp2 of galanin interacts with His264 of the receptor, and Tyr9 is involved in an aromatic-aromatic type of interaction with Phe282 of ECIII of GalR1.

Side chain methyl substitution in the delta-opioid receptor antagonist TIPP has an important effect on the activity profile.

The delta-opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP-OH) or its C-terminal amide analogue was systematically modified topologically by substitution of each amino acid residue by all stereoisomers of the corresponding beta-methyl amino acid. The potency and selectivity (delta- vs mu- and kappa-opioid receptor) were evaluated by radioreceptor binding assays. Agonist or antagonist potency were assayed in the mouse vas deferens and in the guinea pig ileum. In the TIPP analogues containing L-beta-methyl amino acids the influence on delta-receptor affinity and on delta-antagonist potency is limited, the [(2S,3R)-beta-MePhe3]TIPP-OH analogue being among the most potent delta-antagonists reported. In the D-beta-methyl amino acid series, the [D-beta-MeTic2] analogues are delta-selective antagonists whereas [D-Tic2]TIPP-NH2 is a delta-agonist. NMR studies did not indicate any influence of the beta-methyl substituent on the conformation of the Tic residue. The [(2R,3S)-beta-MePhe3]TIPP-NH2 is a potent delta-agonist, its C-terminal carboxylic acid analogue being more delta-selective but displaying partial agonism in both the delta- and mu-bioassay. These results constitute further examples of a profound influence of beta-methyl substitution on the potency, selectivity, and signal transduction properties of a peptide.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.

3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.

Mechanism for biotransformation of nonylphenol polyethoxylates to Xenoestrogens in Pseudomonas putida.

A strain of Pseudomonas putida isolated from activated sewage grew aerobically on the xenoestrogen precursor, nonylphenol polyethoxylate (NPEOx, where x is the number of ethoxylate units) as sole carbon source. Comparative growth yields on NPEOav6, NPEOav9, and NPEOav20 (mixtures with average ethoxylate numbers as indicated) were consistent with utilization of all but two ethoxylate units, and the final accumulating metabolite was identified by gas chromatography-mass spectroscopy as nonylphenol diethoxylate (NPEO2). There was no growth on nonylphenol or polyethylene glycols, and there was no evidence for production of carboxylic acid analogs of NPEOx. Biodegradation kinetics measured by high-pressure liquid chromatography (HPLC) for each component in NPEOx mixtures showed that biodegradation proceeded via successive exoscission of the ethoxylate chain and not by direct scission between the second and third ethoxylate residues. The NPEOx-degrading activity was inducible by substrate, and cell extracts of NPEOav9-induced cells were also active on the pure alcohol ethoxylate, dodecyl octaethoxylate (AEO8), producing sequentially, under either aerobic or anaerobic conditions, AEO7, AEO6, AEO5, etc., thus demonstrating that the pathway involved removal of single ethoxylate units. HPLC analysis of 2,4-dinitrophenylhydrazone derivatives revealed acetaldehyde (ethanal) as the sole aldehydic product from either NPEOav9 or AEO8 under either aerobic or anaerobic conditions. We propose a mechanism for biotransformation which involves an oxygen-independent hydroxyl shift from the terminal to the penultimate carbon of the terminal ethoxylate unit of NPEOx and dissociation of the resulting hemiacetal to release acetaldehyde and the next-lower homolog, NPEOx-1, which then undergoes further cycles of the same reaction until x = 2.

Dihydroorotate dehydrogenase inhibitors: quantitative structure-activity relationship analysis.

The main purpose of this study is to analyze the quantitative structure-activity relationship of two series of dihydroorotate dehydrogenase inhibitors (leflunomide and quinoline carboxylic acid analogues), and to determine the structural requirements for optimum activity of these analogues. A new CQSAR program was used in deriving regression equations and calculating the octanol/water partition coefficient and the molar refractivity values. The molecular modeling was performed using the HyperChem program. Statistically significant correlations were obtained using a combination of 3-4 parameters. The structural requirements for optimum activity and critical regions for the inhibitory activity of dihydroorotate dehydrogenase were identified. The quantitative structure-activity relationship analysis demonstrated that two series of dihydroorotate dehydrogenase inhibitors may bind to different binding sites on the enzyme. These results provide a better understanding of dihydroorotate dehydrogenase inhibitor-enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme.

Syntheses of 2,6-anhydro-3-deoxy-5- O-phosphono-3-tetradecanamido-4- O-[( R)-3-(tetradecanoyloxy)tetradecanoyl]-D- glycero-D- ido-heptonic acid, its dimeric analogue, and related compounds

Pyran carboxylic acid analogues of GLA-60 ( 12a, 12b, and 17) and their dimeric analogues ( 21 and 24) were synthesized in a stereocontrolled manner. Compounds 12a and 17 showed endotoxin antagonistic activity toward human monoblastic U937 cells as an index of the inhibition of LPS-induced TNFα production. Compounds 12b and 24 were less active than 12a and 17. Dimeric ester 21 was practically inactive.

Mutagenesis and ligand modification studies on galanin binding to its GTP-binding-protein-coupled receptor GalR1.

In this study, a large number of receptor mutants were generated and several N-terminally modified galanin analogues synthesized to refine the previously proposed binding site model for galanin to its GTP-binding-protein-coupled receptor GalR1. In addition to ligand-binding studies, the functionality of mutant receptors was evaluated by assessing their ability to mediate galaninergic inhibition of isoproterenol-stimulated adenylyl cyclase activity. The His264Ala and Phe282Ala receptor mutants, although deficient in binding in the concentration range of galanin used, remain functional albeit 20-fold less efficient than the wild-type receptor in mediating inhibition of stimulated cAMP production by galanin. The His267Ala mutant is, apart from being deficient in galanin binding, also severely impaired in functional coupling. While His264 and Phe282 seem to be important in forming the binding pocket for galanin, His267 might play a role in forming or stabilizing the active conformation of the GalR1 receptor rather than directly participating in the formation of the binding pocket for galanin. N-terminal carboxylic acid analogues of galanin have low affinity to wild-type GalR1, but substantially increased affinity to the Glu271Lys receptor mutant. This, together with the finding that an alanine substitution of Phe115 in TM III results in a tenfold decrease in affinity for galanin, suggests that the N-terminus of galanin interacts with Phe115. In contrast to the Phe282Ala mutation in TM VII, a conservative mutation of Phe282 to tyrosine did not alter the affinity for galanin. Thus, the interaction between Tyr9 of galanin and Phe282 is likely to be of an aromatic-aromatic nature.

ChemInform Abstract: Suramin Analogues with a 2‐Phenylbenzimidazole Moiety as Partial Structure. Part 1. Carboxylic Acid Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enzymatic Transformations of Thio Acids and Thio Esters

Enzyme-catalyzed esterifications of thio and carboxylic acid analogues and thiotransesterifications are studied using a commercial immobilized Mucor mieheilipase preparation in an organic solvent. For identical conditions, thio acids are found to react with butanol at rates much faster than those for the corresponding carboxylic acids, suggesting that these substrates could be used to increase the rate of lipase-catalyzed ester syntheses. Enzymatic reactions of butanol and (S) -3-(acetylthio) -2-methylpropionic acid were found to occur via a complex mechanism leading to the formation of multiple products. This reaction appears to occur in a sequential manner, following a parallel-consecutive mechanism yielding initially the carboxylic acid butyl ester and later the deacetylated thiomethylpropionic acid butyl ester.

Synthesis of 2,6-anhydro-3-deoxy-5- O-phosphono-3-tetradecanamido-4- O-[( R)-3-(tetradecanoyloxy)tetradecanoyl]-d- glycero-d- ido-heptonic acid as a new potent endotoxin antagonist and its dimeric analogue

A pyran carboxylic acid analogue of GLA-60 ( 14) and its dimeric analogue 18 were synthesized in a stereocontrolled manner. Compound 14 showed strong LPS-antagonistic activity.

Synthesis and radioprotective properties of 9a-homo-13-thiaprostanoids

Among bioregulators used in the treatment of irradiationinduced diseases [I] a special position belongs to prostaglandins (and especially to their analogs) [2, 3]. These compounds, even taken at extremely low doses, exhibit a combination of therapeutic properties (cytoprotective activity with respect to epithelium of the gastroenteric tract, endothelium of blood vessels, thrombocytes, tissue basophils, immunocompetent cells, etc.). In this connection, we may expect that prostaglandin-based radioprotectors would combine various mechanisms in protecting the organism, together with low toxicity and the absence of side effects. One of the most justified approaches to modification of prostaglandins, which proved to provide an increase in their efficiency, selectivity, and the chemical and metabolic stability, is that based on the replacement of carbon by heteroatoms (N, S, O) [4] and the introduction of alkyi substituents into various sites of the prostanic skeleton [5]. in this work we used both methods for the synthesis of previously unreported 9a-homo-13-thiaprostanoids l l a h and llla d. We have also studied the radioprotective properties of these compounds and some other biological effects that can be used in the prophylaxis and therapy of radiation damage. The key compounds for the synthesis of these 13-thiaprostanoids are the previously described vinyl analogs ofcarboxylic acid chloroanhydrides ( l a d), which were used for obtaining 13-azaprostanoids by interaction with amines [6]. Proceeding from these data and using the results reported by Kirchlechner [7], we expected that interaction of chlorovinyldiketones l a d with thiols would also follow the" scheme of vinyl substitution to yield the 13-thiaprostanoids corresponding to the structures of thiols employed. For thiophenol and thiooctanol, it was found that this reaction actually takes place upon treatmem of [a d with a two-fold excess of thiol in a THF solution in the presence of a ten-fold excess of triethylamine.

Structure and gas-phase acidity of oxalic acid and its disila derivative. A theoretical study by means of the DFT quantum theoretical method

Density functional theory at the B3LYP/6-311 + G* level has been used to study the rotational conformers, gas-phase acidities and vibrational spectra of oxalic and disilaoxalic acid. For oxalic acid the geometry with two five-membered intramolecular hydrogen bonds is calculated to have the lowest energy. In the absence of the stabilizing effect of intramolecular H bonds in disilaoxalic acid (due to the elongation of the M–M distance to 2.35 Å) the most stable conformer corresponds to a rectangular structure making the angle between the two SiOOH groups equal to 90°. The energies calculated for stable conformers lie within 4 kcal mol–1. Experimental and B3LYP computed geometries of oxalic acid agree well. Disilaoxalic acid is, according to calculated ionizations of the first and second hydrogen, about 10–25 kcal mol–1 more acidic than its carboxylic acid analogue. Oxalic and disilaoxalic acid are about 15 and 25 kcal mol–1 stronger acids than formic and silanoic acid, respectively. Computed vibrational frequencies for oxalic, formic and silanoic acids were on average 1–3% higher than the observed values.

Inhibition of purified and membrane-bound flavin-containing monooxygenase 1 by (N,N-dimethylamino)stilbene carboxylates.

(E)-[2-(4-(Dimethylamino)phenyl)vinyl]benzenes bearing a nitrile or carboxyl group in the 2', 3', or 4' position were synthesized and tested for substrate activity with purified pig liver flavin-containing monooxygenase (FMO1). Although the nitrile derivatives were too insoluble to saturate the catalytic site at pH 7.4, they appeared to be substrates with K(m)'s somewhat above their maximum solubility (approximately equal to 0.1 mM) in the assay medium. Of the three carboxylic acid analogs, (E)-4-[2-(4(dimethylamino)phenyl)vinyl]benzoic acid had no detectable water solubility at pH 7.4, and measurements were restricted to (E)-3-[2-(4-(dimethylamino)phenyl)vinyl]benzoic acid (DS3CO) and (E)-2-[2-(4-(dimethylamino)phenyl)vinyl]benzoic acid (DS2CO). While DS3CO and DS2CO were substrates, they also inhibited FMO1 turnover. DS3CO was the more effective inhibitor, and at 2 mM it inhibited FMO1 and microsomal-catalyzed oxidation of methimazole (N-methyl-2-mercaptoimidazole) by 80-90%. Kinetic studies indicated that the aminostilbene carboxylates were noncompetitive with both the xenobiotic substrate, methimazole, and NADPH. However, inhibition constants calculated from double reciprocal plots of velocity vs NADPH were K(i)(comp) 130 and 150 microM for DS3CO and DS2CO, respectively, whereas the uncompetitive Ki's were 10-15 times higher, which suggests that inhibition of NADPH binding may be primarily responsible for inhibition of FMO1 by the aminostilbene carboxylates. This model is also consistent with inhibition of cyclohexanone monooxygenase, a bacterial analog of FMO. DS3CO and DS2CO were again noncompetitive with methimazole but primarily competitive with NADPH. The aminostilbene carboxylates had no detectable effects on activity of pig or rat liver NADPH-cytochrome P450 reductase, which suggests that they are not nonspecific flavoprotein antagonists.

Synthesis and pharmacology of highly selective carboxy and phosphono isoxazole amino acid AMPA receptor antagonists.

(RS)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 5) and the selective AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA, 7) have been used as leads for the design and synthesis of a number of potential AMPA receptor antagonists. Two parallel series of AMOA analogs were synthesized, containing either a distal carboxylic acid (compounds 8b-g and 11b) or a phosphonic acid (compounds 9a-g, 10c, and 11c). Pharmacological characterization of the synthesized compounds was carried out using a series of receptor binding assays and by in vitro electrophysiological experiments using the rat cortical slice model. The two analogs with a tert-butyl substituent, (RS)-2-amino-3-[5-tert-butyl-3-(carboxymethoxy)-4-isoxazolyl]pr opi onic acid (ATOA, 8b) and the corresponding phosphonic acid analog ATPO (9b), were the most potent and selective AMPA antagonists within each series. ATOA and ATPO showed IC50 values of 150 and 28 microM, respectively, toward AMPA-induced depolarizations in the cortical slice model compared to IC50 = 320 microM for the parent compound, AMOA. These two new competitive AMPA antagonists were significantly more selective than AMOA, showing no antagonism (up to 1 mM) toward NMDA-induced responses, whereas AMOA (at 1mM) showed weak (19%) inhibition toward NMDA-induced responses. The structure-activity relationships for the two series of compounds revealed considerable differences with respect to the substituents effects, and the phosphonic acid analogs generally exhibited significantly higher potencies compared to the carboxylic acid analogs.

Synthesis and biological evaluation of novel NK‐1 tachykinin receptor antagonists: The use of cycloalkyl amino acids as a template

In the course of a program aimed at synthesizing novel, potent NK-1 tachykinin receptor antagonists, we developed upon a bioactive model by comparing the low energy structures of a series of peptide and nonpeptide Substance P antagonists. The comparison was based on the superimposition of the aromatic rings, assuming that the rest of the molecule behaves predominantly as a template to arrange the key aromatic groups in the right spatial position. A series of 2-aminocyclohexane carboxylic acid analogues were then selected as the best templates for reproducing the postulated bioactive structure, leading to several pseudo-peptides with interesting biological activity. According to the molecular modeling, these compounds exhibit a neat parallel facing of the indolyl and naphthyl groups at about 3 A distance. Ultraviolet absorption and steady state fluorescence measurements support this conclusion, showing a linear correlation between the spectral properties and the binding affinity of these analogues. Stacking of the indole ring with naphthalene gives rise to a complex characterized by a well-defined molar extinction coefficient. Consistently, steady state and lifetime fluorescence measurements suggest that the quenching process is ascribable to ground-state interactions between the chromophores. Implications of the pi stacking propensity of aromatic groups in the biological activity of the compounds examined are briefly discussed.