3-[4′-bromo-(1,1′-biphenyl)-4-y1]-n,n-dimethyl-3- (2-thienyl)-2-propen-1-amine: Synthesis, Cytotoxicity, And Leishmanicidal, Trypanocidal And Antimycobacterial Activities

Current therapies for Chagas' disease, leishmaniasis and tuberculosis are unsatisfactory because of the failure rates, significant toxicity and/or drug resistance. In this study, the compound 3-[4′-bromo- (1,1′-biphenyl)- 4-yl] -N,N-dimethyl-3- (2-thienyl) -2-propen-1-amine (IV) was synthesized and its trypanocidal, leishmanicidal and antimycobacterial activities were investigated. The cytotoxicity was determined on V79 cells with three endpoints: nucleic acid content, 3-(4,5-dimethylthiazole- 2-yl)-2,5-diphenyl tetrazolium bromide reduction and Neutral Red uptake. This compound was active against different species of mycobacteria and different life cycle stages of Trypanosoma cruzi. In experiments with trypomastigotes performed at 4° C in the presence of blood, the activity was 8.8-fold more active than the standard drug, Crystal Violet. Higher activity was achieved against Leishmania amazonensis, with an ED50/24 h of 3.0 ± 0.3 μmol/L. The effect against trypanosomatids, which suggests high activity of compound IV against promastigotes of L. amazonensis and amastigotes of T. cruzi, stimulated further studies in vitro with amastigotes interiorized in macrophages and with in vivo models. Our results indicate that mammalian V79 cells are less susceptible to the action of compound IV than promastigotes of L. amazonensis (8.0-13.3-fold) and axenic amastigotes of T. cruzi (3.5-5.9-fold).505629637Bleed, D., Watt, C., Dye, C., (2000) Global Tuberculosis. Control, 275, pp. 1-175. , WHO/CDS/TB/2000 Geneva, SwitzerlandGbayisomore, A., Lardizabal, A.A., Reichman, L.B., Update: Prevention and treatment of tuberculosis (2000) Current Opinion in Infectious Disease, 13, pp. 155-159(1998) Weekly Epidemiology Records, 1-2, p. 1. , World Health Organization. Chagas diseaseAlbrecht, H., Sobottka, I., Emminger, C., Jablonowski, H., Just, G., Stoehr, A., Visceral leishmaniasis emerging as an important opportunistic infection in HIV-infected persons living in areas nonendemic for Leishmania donovani (1996) Archives of Pathology and Laboratory Medicine, 120, pp. 189-198Badri, M., Ehrlich, R., Wood, R., Pulerwitz, T., Maartens, G., Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area (2001) International Journal of Tuberculosis and Lung Disease, 5, pp. 225-232Espinal, M.A., Laszlo, A., Simonsen, L., Boulahbal, F., Kim, S.J., Reniero, A., Global trends in resistance to antituberculosis drugs (2001) New England Journal of Medicine, 344, pp. 1294-1303Thomas, S.M., McPhee, D.G., Crystal violet: A direct-acting frameshift mutagen whose mutagenicity is enhanced by mammalian metabolism (1984) Mutation Research, 140, pp. 165-167De Castro, S.L., The challenge of Chagas' disease chemotherapy: An update of drugs assayed against Trypanosoma cruzi (1993) Acta Tropica, 53, pp. 83-98Urbina, J.A., Chemotherapy of Chagas' disease: The how and the why (1999) Journal of Molecular Medicine, 77, pp. 332-338Croft, S.L., Pharmacological approaches to antitrypanosomal chemotherapy (1997) Memórias Do Instituto Oswaldo Cruz, 94, pp. 215-220Leon, L.L., Machado, G.M.C., Barral, A., Carvalho-Paes, L.E., Grimaldi G., Jr., Antigenic differences among Leishmania amazonensis isolates and their relationship with the clinical forms of the disease (1992) Memórias Do Instituto Oswaldo Cruz, 87, pp. 229-234Olliaro, P.L., Bryceson, A.D.M., Practical progress and new drugs for changing patterns of leishmaniasis (1993) Parasitology Today, 9, pp. 323-328Pereira, D.G., De Castro, S.L., Durán, N., Activity of N,N-dimethyl-1-2- propen-1-amine derivatives in mice experimentally infected with Trypanosoma cruzi (1998) Acta Tropica, 69, pp. 205-211De Souza, A.O., Santos Júnior, R.R., Ferreira-Júlio, J.F., Rodriguez, J.A., Melo, P.S., Haun, M., Synthesis, antimycobacterial activities and cytotoxicity on V79 of 3-(4′-bromo1,1m-biphenyl-4-yl)-3- (4-x-phenyl)- N,N-dimethyl- 2-propen-1-amine derivatives (2001) European Journal of Medicinal Chemistry, 36, pp. 843-850De Souza, A.O., Durán, N., Synthesis and antileishmaniasis activities of N,N-dimethyl- 2-propen-1-amine derivatives (1998), Brazilian Patent PIBr. 9902748-8De Souza, A.O., Sato, D.N., Aily, D.C.G., Durán, N., In vitro activity of N,N-dimethyl- 2-propen-1-amines against Mycobacterium tuberculosis (1998) Journal of Antimicrobial Chemotherapy, 42, pp. 407-408De Conti, R., Gimenez, S.M.N., Haun, M., Pilli, R.A., De Castro, S.L., Durán, N., Synthesis and biological activities of N,N-dimethyl-2- propen-1-amine derivatives (1996) European Journal of Medicinal Chemistry, 31, pp. 1-4Cingi, M.R., De Angelis, I., Fortunati, E., Reggiani, D., Bianchi, V., Tiozzo, R., Choice and standardization of test protocols in cytotoxicology: A multicentre approach (1991) Toxicology In Vitro, 5, pp. 119-125Denizot, F., Lang, R., Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability (1986) Journal of Immunological Methods, 89, pp. 271-277Borenfreund, E., Puerner, J.A., A simple quantitative procedure using monolayer cultures for cytotoxicity assays (HTD/VN 90) (1984) Journal of Tissue Culture Methods, 9, pp. 7-9Collins, L.A., Franzblau, S.G., Microplate Alamar Blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium (1997) Antimicrobial Agents and Chemotherapy, 41, pp. 1004-1009Silva, L.H.P., Nussenszweig, V., Sobre uma cepa de Trypanosoma cruzi virulenta para o camundongo branco (1953) Folia Clinica Biologica, 20, pp. 191-207De Castro, S.L., Meirelles, M.N.L., Oliveira, M.M., Trypanosoma cruzi: Adrenergic modulation of cAMP role in proliferation and differentiation of amastigotes in vitro (1987) Experimental Parasitology, 64, pp. 368-375De Castro, S.L., Pinto, M.C.F.R., Pinto, A.V., Screening of natural and synthetic drugs against Trypanosoma cruzi. 1-Establishing a structure/activity relationship (1994) Microbios, 78, pp. 83-90De Castro, S.L., Soeiro, M.N.C., Higashi, K.O., Meirelles, M.N.L., Differential effect of amphotericin B on the three evolutive stages of Trypanosoma cruzi and on the host cell-parasite interaction (1993) Brazilian Journal of Medical and Biological Research, 26, pp. 1219-1229Grimaldi G., Jr., David, J.R., McMahon-Pratt, D., Identification and distribution of New World Leishmania species characterized by serodeme analysis using monoclonal antibodies (1987) American Journal of Tropical Medicine and Hygiene, 36, pp. 270-287De Reuck, A.V.S., Cameron, M.P., The reversible activation of lysosomes in normal cells and the effect of pathological conditions (1963) Lysosomes, pp. 362-375. , (De Reuck, A. V. S. & Cameron, M. P., Eds) Little, Brown & Co., Boston, MA, USASchlemper, B.R., Chiari, E., Brener, Z., Growth inhibition drug test with Trypanosoma cruzi culture forms (1977) Journal of Protozoology, 24, pp. 544-547De Castro, S.L., Soeiro, M.N.C., Meirelles, M.N.L., Trypanosoma cruzi: Effect of phenothiazines on the parasite and on its interaction with host cells (1992) Memórias Do Instituto Oswaldo Cruz, 87, pp. 209-215Lopes, J.N., Cruz, F.S., Do Campo, R., Vasconcellos, M.E., Sampaio, M.C.R., Pinto, A.V., In vitro and in vivo evaluation of the toxicity of 1,4-naphthoquinone and 1,2-naphthoquinone derivatives against Trypanosoma cruzi (1978) Annals of Tropical Medicine and Parasitology, 72, pp. 523-531Rovai, L.E., Aoki, A., Gerez de Burgos, N.M., Blanco, A., Effect of gossypol on trypomastigotes and amastigotes of Trypanosoma cruzi (1990) Journal of Protozoology, 37, pp. 280-286Neves-Pinto, C., Dantas, A.P., De Moura, K.C.G., Emery, F.S., Polequevitch, P.F., Pinto, M.C.F.R., Chemical reactivity studies with naphthoquinones from Tabebuia with antitrypanosomal efficacy (2000) Arzneimittel- Forschung-Drug Research, 50, pp. 1120-1128Araujo, C.A.C., Alegrio, L.V., Leon, L.L., Antileishmanial activity of compounds extracted and characterized from Centrolobium sclerophyllum (1998) Phytochemistry, 49, pp. 751-754Marsden, P.D., Sampaio, R.N.R., Carvalho, E.M., Veiga, J.P.T., Costa, J.L.M., Llanoscuentas, E.A., High continuous antimony therapy in two patients with unresponsive mucosal leishmaniasis (1985) American Journal of Tropical Medicine and Hygiene, 34, pp. 710-713Afrin, F., Dey, T., Anam, K., Ali, N., Leishmanicidal activity of stearylamine-bearing liposomes in vitro (2001) Journal of Parasitology, 87, pp. 188-193Wiese, M., Gorckel, I., Homologues of LMPK, a mitogen-activated protein kinase from Leishmania mexicana, in different Leishmania species (2001) Medical Microbiology and Immunology, 190, pp. 19-22Croft, S.L., Yardley, V., Chemotherapy of leishmaniasis (2002) Current Pharmaceutical Design, 8, pp. 319-342Loiseau, P.M., Bories, C., Recent strategies for the chemotherapy of visceral leishmaniasis (1999) Current Opinion in Infectious Diseases, 12, pp. 559-564Escobar, P., Matu, S., Croft, S.L., Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH3 (edelfosine) and amphotericin B (2002) Acta Tropica, 81, pp. 151-157Escobar, P., Yardley, V., Croft, S.L., Activities of hexadecylphosphocholine (miltefosine), AmBisome, and sodium stibogluconate (Pentostam) against Lerishmania donovani in immunodeficient scid mice (2001) Antimicrobial Agents and Chemotherapy, 45, pp. 1872-1875Kayser, O., Kiderlen, A.F., Laatsch, H., Croft, S.L., In vitro leishmanicidal activity of monomeric and dimeric naphthoquinones (2000) Acta Tropica, 77, pp. 307-314Valderrama, J., Fournet, A., Valderrama, C., Bastias, S., Astudillo, C., De Arias, A., Synthesis and in vitro antiprotozoal activity of thiophene ring-containing quinones (1999) Chemical and Pharmaceutical Bulletin, 47, pp. 1221-1226Ram, V.J., Goel, A., Shukla, P.K., Kapil, A., Synthesis of thiophenes and thieno[3,2-c]pyran-4-ones as antileishmanial and antifungal agents (1997) Bioorganic and Medicinal Chemistry Letters, 7, pp. 3101-3106Nussbaumer, P., Ryder, N.S., Stutz, A., Allylamine antimycotics-recent trends in structure- activity-relationships and syntheses (1991) Pesticide Science, 31, pp. 437-455Nussbaumer, P., Petranyi, G., Stutz, A., Synthesis and structure-activity- relationships of benzo[b]thienylallylamine antimycotics (1991) Journal of Medicinal Chemistry, 34, pp. 65-73Stutz, A., Georgopoulos, A., Granitzer, W., Petranyi, G., Berney, D., Synthesis and structure-activity relationships of naftifine-related allylamine antimycotics (1986) Journal of Medicinal Chemistry, 29, pp. 112-12

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally