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N-Methyl-N-2-propynyl-1-naphthalenecarboxamide, N-methyl-N-2-propynyl-1-naphthaleneacetamide, and N-methyl-N-3-butynyl-1-naphthalenecarboxamide undergo intramolecular Diels-Alder reactions at 190°, 250°, and 270° to give lactams 1,6, and 9, respectively. The cyclization temperatures are higher by 80-120° as compared to those of the corresponding anthracene derivatives. Elaboration of lactam 6 gave the trans-4a-aryldecahydroisoquinoline derivative 7a which, as the (-) isomer, was shown to have the same absolute stereochemistry as morphine.

A novel series of 2-indolinones with in vitro anti-HIV (human immunodeficiency virus) activity is described. Two structurally related compounds, 1, 3,3-(4- N-methyl-1,2,5,6-tetrahydropyridylmethyl)-1- phenyl-2-indolinone, and 2, its 4- N-methylpiperidinylmethyl analogue (Fig. 1), formed the basis of a structure-activity study. The synthesis of approximately 50 analogues and their respective activities vs. HIV are presented. Both 1 and 2 were effective inhibitors of HIV(IIIb) in cell protection assays with IC90 values of 4.4 and 14.9μM (2.2 and 7.9μg ml−1), respectively. In the same concentration range, 1 and 2 also inhibit syncytia formation. These compounds represent a novel class of anti-HIV agents which appear to act by inhibiting virus-dependent cell fusion.

N-Methyl-N-propargylimidazole-5-carboxamide undergoes thermal intramolecular Diels-Alder reaction to give the title compound. A related reaction of the corresponding sydnone system is also described.

A number of analogs of the cognition enhancing agent DuP 996 were prepared by varying the core structure and pendant groups in an independent fashion. The SAR of 2-, 3-, and 4-pyridinylmethyl groups as pendant groups on selected cores was examined.

The results of a detailed study of the structure-activity relationships in the series of compounds represented by DuP 747 are described.

The synthesis and structure-activity relationship (SAR) studies of the effect of different polysubstitution patterns in the aromatic ring of 5-(acetamidomethyl)oxazolidinone antibacterials (I) on antibacterial activity are presented. Compounds I were prepared by the six-step synthesis described previously (Gregory, W. A.; et al. J. Med. Chem. [formula: see text] 1989, 32, 1673), electrophilic aromatic substitution reactions of 3-substituted compounds, and functional-group interchange reactions of 3,4-disubstituted compounds. Antibacterial evaluation of compounds I against Staphylococcus aureus and Enterococcus faecalis gave the following results. The 2,4- and 2,5-disubstituted derivatives have weak or no antibacterial activity. Antibacterial activities of 3,4-disubstituted compounds are comparable to those of the 4-monosubstituted analogues for small 3-substituents (smaller than Br), but decline rapidly for larger 3-substituents. 3,4-Annulated derivatives are comparable in activity to their open-chain analogues. 3,5-Disubstituted and 3,4,5- and 2,4,6-trisubstituted derivatives are devoid of antibacterial activity.

The synthesis and structure-activity relationship (SAR) studies of the effect of varying the "A" group in a series of 5-(acetamidomethyl)oxazolidonone antibacterials (2) are described. Compounds 2 were principally prepared either by the six-step synthesis described previously (J. Med. Chem. 1989, 32, 1673) or by elaboration of the synthetic intermediate 2 (A = H) via electrophilic aromatic substitution or elaboration of the intermediate 2 (A = I) by transition metal catalyzed carbon-carbon bond-forming reactions. Antibacterial evaluation of compounds 2 with A = alkyl, ethenyl, ethynyl, hydroxyalkyl, aldo and keto, oximinoakyl, carboalkoxy, nitro, amino, halo and psi-halo, alkylthio, alkylsulfinyl, and alkysulfonyl against Staphylococcus aureus and Enterococcus faecalis led to the identification of several SAR trends. In several series of homologues (alkyl, ketyl, aximinoalkyl, amino, halo and psi-halo, and alkythio), antibacterial activity increased with increasing lipophilicity. But in series with where A is a substituent with a trior tetrasubstituted (substituent larger than H) quaternary atom attached directly to the aromatic ring (hydroxyalkyl, alkylsulfinyl, alkylsufonyl), the activity peaked at the member of the series with the "tert-butyl" connectivity pattern. Conjugated electron-withdrawing substituents also had increased activity relative to nonconjugated analogues of comparable lipophilicity.

Some new phenothiazines have been synthesized on the basis of previous studies. The anticancer activity of "half-mustard type" phenothiazines was investigated on sixty different cancer cell lines in vitro. The percentage of growth (PG), 50% inhibition of growth (GI50), the tumor growth inhibition (TGI) and the concentration required for 50% lethality of cells (IC50) were examined and calculated in the presence of various (from 10(-4) to 10(-8) M) concentrations of phenothiazine alkylurea derivatives. The following cell lines were involved in the study: 6 leukemia, 9 non-small-cell lung cancer, 7 colon cancer, 6 central nervous system cancer, 8 melanoma, 6 ovarian cancer, 8 renal cancer, 2 prostate and 8 breast cancer cell lines. The antileukemic activity of four chloroethyl-substituted phenothiazine-alkylureas was shown by considerable growth inhibition, in the 10(-5) M range, of the six different leukemia cell lines. The 50% inhibition of growth was nearly the same for the four compounds on all cell lines. Tumor growth inhibition (TGI) and IC50 value to cells varied from -4.0 to -4.66. The two derivatives with the butylene bridge were more effective than propylene linked compounds against the CCRP-CEM, HL60 (TB), K-562 and MOLT-4 cell lines. However, the anti-leukemic activity of the derivatives was nearly the same for RPMT 8226 and SR cell lines. The substituent at the 2- position of phenothiazine ring and the length of the linker between the side chain nitrogen and the phenothiazine ring system are apparently important for antileukemic activity. Four of the 9 non-small-cell lung cancer cell lines were sensitive, while the other 5 cell lines were not. The compounds had a slight growth inhibitory effect on colon cell carcinoma and melanoma cells in which case the butylene linker seemed to be more effective than the propylene linker. At the same time, all of the compounds were weak or mostly inactive on cancer cells from the central nervous system. One ovarian cancer line of the 6, the IGROVI was sensitive to butylurea phenothiazines, however, the other five were not sensitive at all. The difference in the sensitivity of various renal cell carcinomas was significant: 5 lines were not sensitive, three of them (786-0, RXF-393 and TK-10) were sensitive to only butylene-substituted phenothiazine-ureas, propylene substitution resulted in ineffective compounds. The compounds were not able to inhibit the 2 prostate and 4 breast cancer cell lines, even at 10(-4) M. It was interesting that propylene-linked ureas were more effective than butylene-linked derivatives on MCF-7, but butylene-linked derivatives were more effective than propylene-linked compounds on MDA MB-231 and MDA-N. In addition, MDA MB 435 was more sensitive to the trifluoromethyl derivatives than the compounds without this substituent. Since the phthalimido-alkyl phenothiazines were not active at the first level of prescreen, these compounds were omitted from this study. The drug sensitivity of some cancer cell lines was not uniform for the different groups, therefore we postulate that the resistance can be related to some kind of (existing) drug-efflux mechanism. Apparently, the tumor specificity of phenothiazine alkylureas is more related to the leukemia specificity of alkylureas than to any CNS or lung specificity of phenothiazines.

The antitumor effects of "half-mustard type" phenothiazines were studied on 57 different tumor cell lines, including leukemias, non-small lung cancer, colon, central nervous system, ovarian, renal, breast, and prostate cancer, as well as melanoma cell cultures. Alkyl-urea derivatives of phenothiazines displayed in vitro antitumor activity. The phenothiazine phthalimido derivatives (1-6) were not active on the majority of cancer cell cultures. In contrast, propylureas (9, 11) were active against some leukemia cell types. Only two compounds with the butylene [(CH2)4] linker (10, 12) were active against non-small lung cancer cells. Compounds containing the propylene linker were less effective. On colon cancer lines, tumor cells from the central nervous system and on melanoma cells the same compounds were effective, however, having substituents at the 2-position of phenothiazine seems to be important. Surprisingly, the majority of ovarian cancer cell lines (except one type, IGROVI) and five of eight renal cancer lines were not sensitive to these phenothiazine derivatives. The two butylene linked phenothiazine ureas (10, 12) had moderate antiproliferative action on two renal cancer cell lines. The prostate cancer and some breast cancer cell lines were not sensitive. Nevertheless some breast cancer cell lines were apparently sensitive to CF3-substituted phenothiazine alkylureas. On the basis of these experiments one may postulate that in the case of insensitive cells an mdr-gene encoded multidrug resistance efflux pump is responsible for the resistance. The selectivity or organ cell specificity of the effective phenothiazines will be targeted for improvement in further studies, in order to avoid the general cytotoxic effects of "half mustard type" phenothiazines.

Twelve different "half-mustard type" phenothiazines were newly synthesized and tested on seven AIDS-related lymphoma (ARL) tumor cell lines, one leukemia CCRF-CEM cell culture and five different lymphoma lines; RL, KD-488, AS283, PA682 and SU-DHL-7 cell lines. The alkylene-urea substituted phenothiazines affected the growth and inhibited the growth rate of AIDS-related lymphoma cells. The Cl-substituent at the 2-position was more effective than the CF3 substitution. In AIDS-related leukemia also the compounds with Cl at the 2-position with propylene or butylene linkers, -(CH2)3- and -(CH2)4-, respectively, were more effective than the CF3 substituted compounds. Two of the six phenothiazine-substituted alkyl-urea derivatives, i.e., 1-(2-chloroethyl)-3-(2-chloro-10H-phenothiazin-10-yl)propyl-l-urea (9, GI50 = -5.66, TGI = -5.04) and 1-(2-chloroethyl)- 3-(2-chloro-10H-phenothiazin-10-yl)butyl-1-urea (10, GI50 = -5.61, TGI = -5.12) exhibited antitumor activity for AIDS-related leukemia and five AIDS-related lymphomas. The trifluoromethyl-substituted derivatives were not as effective on AIDS-related tumor cell lines. Apparently, the substituent at the 2-position on the phenothiazine and the alkylene number of the linker attached to the nitrogen of the phenothiazine ring have an important role in the compound's antitumor effects on AIDS-related leukemia and lymphomas.

We have synthesized a promising class of bis-naphthalimide anti-tumor agents. A representative compound in this series, XB596, exhibits potent in vitro growth inhibitory activity against several human and murine leukemic and solid tumor lines in culture, with IC50 values ranging from 7.2 to 147.5 nM. XB596 was almost as equally growth inhibitory against three doxorubicin-resistant cell lines compared with their parental lines. Using a human tumor colony-forming assay, XB596 demonstrated cytocidal activity against fresh human tumors taken directly from patients, with 23 of 25 evaluable tumors responding to a continuous exposure of 1 microgram/ml of XB596. When L1210 cells were incubated with XB596 for 1 h, the incorporation of uridine and thymidine into RNA and DNA, respectively, was inhibited with IC50 values of 0.14 microM. DNA single-strand breaks, but not double-strand breaks, were detected in XB596-treated L1210 cells. XB596 bound to DNA with guanine-cytosine sequence selectivity as shown by an indirect ethidium bromide displacement assay. XB596 was shown to interact with DNA by a spectrophotometric titration assay, with an estimated binding constant of 4.7 +/- 2.2 +/- 10(6) M-1. XB596 unwound supercoiled DNA as measured by agarose gel electrophoresis. These data are consistent with XB596 being a DNA intercalator. In vivo, XB596 demonstrated good anti-tumor activity against two human solid tumors (DLD-2 colon adenocarcinoma and MX-1 mammary carcinoma) xenografted in nude mice, but has not demonstrated anti-leukemic activity. In summary, XB596 is a pre-clinical anti-cancer agent which interacts with DNA and demonstrates good in vivo anti-tumor activity against human solid tumor xenografts.

N-Methyl-N-propargylimidazole-5-carboxamide undergoes thermal intramolecular Diels-Alder reaction to give the title compound. A related reaction of the corresponding sydnone system is also described.

The synthesis and structure/activity studies of the effect of varying the "B" group in a series of oxazolidinone antibacterials (I) are described. Two synthetic routes were used: (1) alkylation of aniline with glycidol followed by dialkyl carbonate heterocyclization to afford I (A = H, B = OH), whose arene ring was further elaborated by using electrophilic aromatic substitution methodology; (2) cycloaddition of substituted aryl isocyanates with epoxides to give A and B with a variety of values. I with B = OH or Br were converted to other "B" functionalities by using SN2 methodology. Antibacterial evaluation of compounds I with A = acetyl, isopropyl, methylthio, methylsulfinyl, methylsulfonyl, and sulfonamido and a variety of different "B" groups against Staphylococcus aureus and Enterococcus faecalis concluded that the compounds with B = aminoacyl, and particularly acetamido, were the most active of those examined in each A series, possessing MICs in the range of 0.5-4 micrograms/mL for the most active compounds described.

A chiral synthesis of DuP 721 [(S)-N-[3-(4-acetylphenyl)-2-oxo-5-oxazolidinylmethyl]acetamide] from 4-acetylphenyl isocyanate ( 1 ) and (R)-glyddyl butyrate ( 2 ) is described.

DuP 721 (p-acetylphenyloxooxazolidinylmethylacetamide) and DuP 105 (a methylsulfinyl derivative) are orally active representatives of the oxazolidinones, a new class of synthetic antibacterial agents. Their antibacterial spectrum includes staphylococci, streptococci, and Bacteroides fragilis strains. The compounds have equal activity against staphylococcal strains susceptible or resistant to beta-lactam antibiotics, including methicillin-resistant strains. The MICs for 90% of the strains (MIC90s) against staphylococcal isolates were 1 to 4 micrograms/ml for DuP 721 and 4 to 16 micrograms/ml for DuP 105, compared with 1 to 2 micrograms/ml for vancomycin, 0.5 microgram/ml for ciprofloxacin, and 2 to greater than 16 micrograms/ml for imipenem. The MIC90s against group D streptococci were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 2 micrograms/ml for vancomycin, ciprofloxacin, and imipenem. MIC90s against B. fragilis isolates were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 8 micrograms/ml for cefoxitin. DuP 721 and DuP 105 administered by either the oral or the parenteral route were protective against staphylococcal and streptococcal infections in mice. The 50% effective doses were 2 to 10 mg/kg for DuP 721, 9 to 23 mg/kg for DuP 105, and 2 to 12 mg/kg for vancomycin. These results indicate that further studies of compounds of the oxazolidinone series are warranted.

A chiral synthesis of DuP 721 [(S)-N-[3-(4-acetylphenyl)-2-oxo-5-oxazolidinylmethyl]acetamide] from 4-acetylphenyl isocyanate ( 1 ) and (R)-glyddyl butyrate ( 2 ) is described.