title: Synthesis of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as potential antitumor and antifungal agents.
abstract: A new series of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines 6a-g and 7a-g were obtained with high regioselectivity from the reaction of triamino- or tetraaminopyrimidines 4 and 5 with α,β-unsaturated carbonyl compounds 3a-g based on 2,4-dichlorothiazol-5-carbaldehyde 1. Twelve of the synthesized compounds were selected and tested by US National Cancer Institute (NCI) for their antitumor activity against 60 different human tumor cell lines. Compounds 7d and 7g showed important GI50 ranges of 1.28-2.98 μM and 0.35-2.78 μM respectively under in vitro assays. In addition, 6a-g and 7a-g were tested for antifungal properties against the clinical important fungi Candida albicans and Cryptococcus neoformans. Although these compounds showed moderate activities against C. albicans, the 2-amino derivatives 7a-g and mainly 7a and 7b, showed high activity against standardized and clinical isolates of C. neoformans with MIC50 = 7.8-31.2 μg/mL, MIC80 = 15.6-31.2 μg/mL and MIC100 = 15.6-62.5 μg/mL. In addition, since both compounds were fungicide rather than fungistatic these thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines appear as good candidates for further development not only as antifungal but also as antitumor drugs.
authors: Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia.
authors: Juan
authors: J
authors: Ramírez
authors: Área Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
authors: Laura
authors: L
authors: Svetaz
authors: Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia.
authors: Jairo
authors: J
authors: Quiroga
authors: Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia.
authors: Rodrigo
authors: R
authors: Abonia
authors: Área Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
authors: Marcela
authors: M
authors: Raimondi
authors: Área Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
authors: Susana
authors: S
authors: Zacchino
authors: Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia. Electronic address: braulio.insuasty@correounivalle.edu.co.
authors: Braulio
authors: B
authors: Insuasty
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D001381:Azepines; D011743:Pyrimidines; D013844:Thiazoles
keywords: Antifungal activity; Antitumor activity; Pyrimido[4,5-b][1,4]diazepines; Regioselectivity; Thiazole