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Quantitative relationships (QSAR) have been derived between antileukemic (L1210) activity and agent physicochemical properties for 509 tumor-active members of the general class of 9-anilinoacridines. One member of this class is the clinical agent m-AMSA (NSC 249992). Agent hydrophobicity proved a significant but not a dominant influence on in vivo potency. The electronic properties of substituent groups proved important, but the most significant effects on drug potency were shown by the steric influence of groups placed at various positions on the 9-anilinoacridine skeleton. The results are entirely consistent with the physiologically important step in the action of these compounds being their binding to double-stranded DNA by intercalation of the acridine chromophore between the base pairs and positioning of the anilino group in the minor groove, as previously suggested. An equation was also derived for the acute toxicities of 643 derivatives of 9-anilinoacridine. This equation took a somewhat similar form to the one modeling antileukemia potency, emphasizing the usual fairly close relationship between potency and acute toxicity for antitumor agents in general. This study demonstrated the power of QSAR techniques to structure very large amounts of biological data and to allow the extraction of useful information from them bearing on the possible site of action of the compounds concerned.

Heparanase is the sole mammalian enzyme capable of cleaving glycosaminoglycan heparan sulfate side chains of heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar concentration, and the most promising compounds are fluorinated and/or amino acids derivatives 13a, 14d, and 15 that showed IC 0.16-0.82 μM. Molecular docking studies were performed to rationalize their interaction with the enzyme catalytic site. Importantly, invasion assay confirmed the antimetastatic potential of compounds 14d and 15. Consistently with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF, and FGFs in tumor cells.

Heparanase is the only mammalian endo-β-D-glucuronidase involved in a variety of major diseases. The upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, representing a validated target in the anti-cancer field. To date, only a few small-molecule inhibitors have been described, but none have gotten through pre-clinical development. Previously, we explored 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as antiheparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Herein, we report an extended investigation of new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivatives, proving that symmetrical compounds are more effective than asymmetrical analogues, with the most-potent compound, 7g, being active at nanomolar concentration against heparanase. Molecular docking studies were performed on the best-acting compounds 5c and 7g to rationalize their interaction with the enzyme. Moreover, invasion assay confirmed the anti-metastatic potential of compounds 5c, 7a, and 7g, proving the inhibition of the expression of proangiogenic factors in tumor cells.

Objective: To evaluate the comparative diagnostic value of harmonic imaging (HI) in the assessment of patients with suspected infective endocarditis (IE). Setting: Tertiary referral centre. Design: 139 consecutive patients were evaluated with three imaging modalities: transthoracic echocardiography with fundamental imaging (FI); HI; and transoesophageal echocardiography (TOE). Image quality was assessed for each modality by semiquantitative scoring (0, poor, to 3, excellent). Presence, dimension, and characteristics of vegetations were assessed separately for each imaging modality, as well as presence of abscesses. Results: 35 patients had definite IE. TOE was positive in 33 patients, HI in 28, and FI in 12 (p , 0.001 for FI v HI and v TOE). Mean image quality was 1.4 (0.7) for FI, 2.1 (0.6) for HI (p , 0.01 v FI), and 2.6 (0.4) for TOE (p , 0.001 v HI). The association between FI and TOE findings was W = 0.35 (x 2 = 17.57, p = 0.0014) and between HI and TOE it was W = 0.95 (x 2 = 125.72, p , 0.0001; p , 0.0001 v FI). The global echo score of vegetations was 7.1 (3.3) with FI, 8.5 (3.4) with HI, and 11.3 (3.9) with TOE (p , 0.001 v HI). Compared with TOE, FI identified only one of seven abscesses (sensitivity 14%) and HI identified two of seven abscesses (sensitivity 28%). Conclusions: HI provides an accurate assessment of suspected IE. TOE achieves superior definition of IE related abnormalities. D espite advances in diagnosis and treatment, infective endocarditis (IE) still has high morbidity and mortality often due to delayed diagnosis.

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We have designed and synthesized a series of new imidazole-based compounds structurally related to an antiprotozoal agent with nanomolar activity which we identified recently. The new analogues possess micromolar activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar potency against Plasmodium falciparum. Most of the analogues displayed IC50 within the low nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure–activity relationships and in vitro biological data for the new compounds are provided against a number of different protozoa. The mechanism of action for the most potent derivatives (5i, 6a–c, and 8b) was assessed by a target-based assay using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits were assessed in a T. cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal administration of 25 mg/kg/day dose for 4 consecutive days.

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