Synthesis of new pyrazoles, oxadiazoles, triazoles, pyrrolotriazines, and pyrrolotriazepines as potential cytotoxic agents

Abstract

4‐Oxo‐4‐phenylbutanehydrazide (1) reacted with many active methylene reagents such as acetylacetone, diethylmalonate, ethylacetoacetate, ethylcyanoacetate, benzoyl‐acetonitrile, and malononitrile under neat conditions to afford the corresponding pyrazoles (2–7), also, treatment of butanehydrazide (1) with electrophilic reagents as triethylorthoformate, dimethylformamide‐dimethylacetal, acetic anhydride, and carbon disulfide to give 1,3,4‐oxadiazoles (8,10,11) and N′‐acetyl‐butanehydrazide (9). Reacted of butanehydrazide (1) with potassium thiocyanate gave 1,2,4‐triazoles (12). Similarly, treatment of (1) with chloroacetamide gave 1,2,4‐triazinones (13). The pyrrolotriazinones (14) was obtained by cyclization of (13). Also, butanehydrazide (1) was utilized as a starting material for the synthesized of new Schiff bases as N′‐(4‐sub‐benzylidene)‐phenylbutane‐hydrazide (15a‐c), which are used as an initiative to prepare new compounds such as 1,2,4‐triazepinones (16a‐c), pyrrolotriazepinones (17a‐c), 1,2,4‐triazines (18a‐c), and pyrrolotriazines (19a‐c) by reacted of (15a‐c) with each chloroacetamide or formamide. The chemical structure of the newly prepared compounds was determined through the spectrum data, including IR, NMR, and MS. The prepared compounds were tested for their in vitro antitumor activities. The compounds 17a‐c, 16a‐c, and 19a‐c displayed activity against several types of cancer cell lines.

Design, Synthesis and Anticancer Activity of New Polycyclic: Imidazole, Thiazine, Oxathiine, Pyrrolo-Quinoxaline and Thienotriazolopyrimidine Derivatives

“…The relationship of the chemical structures (SARs) of the prepared compounds to the results mentioned in this study, in terms of the ability of these compounds to apply cytotoxicity activity to human carcinoma cells, is due to several possibilities, including the following: (A) The presence of the thienopyrimidinones, 1,2,4-triazolopyrimidinone, 1,4-thiazine, pyrrolo-1,2,4-triazole, pyrroloquinoxaline, oxathiinoquinoxaline, 1,4-oxathiinopyrrolotriazole, imidazopyrrolotriazole and 1,2,4-triazoloimidazopyrrolo-triazole moieties may be requested for a broad spectrum of the cytotoxicity activity. (B) 1,2,4triazoloimidazopyrrolotriazolothienopyrimidindione (20), imidazopyrrolotriazolo-thienopyrimidindione (19), thienopyrimidotriazolopyrrolooxathiinoquinoxalindione (17), thienopyrimidotriazolopyrroloquinoxalindione ( 16), 2-(((6-benzoyl-thienotriazolo-pyrimidin-2yl)methyl) thio)-thienotriazolopyrimidinene (11) and 1,4-oxathiinopyrrolo-triazolothienopyrimidin-trione ( 18) demonstrated great anticancer activity in vitro, and this corresponds to previous scientific studies, because numerous heterocyclic compounds have pharmacological activities, such as imidazoles, benzimidazoles, thieno-[2,3-d]pyrimidines, 1,2,4-triazoles, thiazolopyrimidines, pyrrolothiazolo-pyrimidines, pyrrolotriazines, pyrrolotriazepines, triazolopyrrolothiazolopyrimidines, quinolines, quinoxalines, thiazolidinones, thiazines, thienotriazoles, thiophenes, phenyl, benzoyl and methyl, which have displayed potent anticancer activity [2,5,8,10,20,25,34,38,40,[48][49][50]. (C) Thence, the compounds 20, 19, 17, 16, 11 and 18 offered high cytotoxicity against all human carcinoma cell lines, such as nasopharyngeal (CNE2), oral (KB), breast (MCF-7) and gastric (MGC-803), during the comparison with 5-Fluorouracil as a standard drug, shown in Table 2.…”

“…Moreover, the reaction of pyrrolotriazolothienopyrimidine-4,7-dione (15) with thiourea in a mixture of dimethylformamide or dioxane in the presence of catalytic amount of piperidine under control (TLC) afforded the 7-benzoyl-2-mercapto-8-methyl-1H-imidazo[4",5": (19). The IR spectrum of compound 19 displayed the presence of broad band absorption at ν 3355 cm −1 of one (NH) group, 2357 cm The new compounds that were synthesized, such as thieno [2,3-d]pyrimidinones, thienotriazolopyrimidinones, thienopyrimido-triazolo-thiazines, pyrrolo-triazolothieno-pyrimidines, thieno-pyrimido-triazolopyrrolo-quinoxalines, thieno-pyrimidotriazolo-pyrrolo-oxathiino-quinoxalines, 1,4-oxathiino-pyrrolotriazolo-thienopyrimidin-triones, imidazopyrrolotriazolothienopyrimidin-diones and 1,2,4-triazoloimidazopyrrolotriazol-othienopyrimidin-diones, were tested for their in vitro cytotoxicity using the standard method to test cell growth rate and toxicity of the culture (MTT) method [34,38,40,48] against the human nasopharyngeal carcinoma cells (CNE2), oral carcinoma cells (KB), breast adenocarcinoma cells (MCF-7) and gastric carcinoma cells (MGC-803). The MTT method is based on the reduction of soluble 3-(4,5dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, as shown in Table 1.…”

“…The in vitro cytotoxicity of the synthesized compounds against different cancer cell lines was performed with the MTT assay, according to the method found in [34,38,40,48]. The MTT assay is based on the reduction of the soluble 3-(4,5-dimethyl-2-thiazolyl)-2,5diphenyl-2H-tetrazoliumbromide (MTT) into a blue-purple formazan product, mainly by mitochondrial reductase activity inside living cells.…”

“…In this manuscript, these compounds, thienotriazolopyrimidinone, thienopyrimidotriazolopyrrolooxathiinoquinoxalines and 1,2,4-triazoloimidazopyrrolotriazolothienopyrimidinedione derivatives were synthesized from 2,3-diamino-6-benzoyl-5-methylthieno [2,3-d]pyrimidinone and evaluated as having antiproliferative activities against types of human carcinoma cancer cell lines. This article is a supplement of our former work about the preparation of heterocyclic compounds resulting from pyrimidine and thienopyrimidine derivatives, which possess biological activities [4,5,8,11,12,[19][20][21][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. In this manuscript, these compounds, thienotriazolopyrimidinone, thienopyrimidotriazolopyrrolooxathiinoquinoxalines and 1, 2, 4triazoloimidazopyrrolotriazolothienopyrimidinedione derivatives were synthesized from 2, 3-diamino-6-benzoyl-5-methylthieno [2, 3-d] pyrimidinone and evaluated as having antiproliferative activities against types of human carcinoma cancer cell lines.…”

“…have pharmacological activities, such as imidazoles, benzimidazoles, thieno-[2,3-d]pyrimidines, 1,2,4-triazoles, thiazolopyrimidines, pyrrolothiazolo-pyrimidines, pyrrolotriazines, pyrrolotriazepines, triazolopyrrolothiazolopyrimidines, quinolines, quinoxalines, thiazolidinones, thiazines, thienotriazoles, thiophenes, phenyl, benzoyl and methyl, which have displayed potent anticancer activity[2,5,8,10,20,25,34,38,40,[48][49][50]. (C) Thence, the compounds 20, 19, 17, 16, 11 and 18 offered high cytotoxicity against all human carcinoma cell lines, such as nasopharyngeal (CNE2), oral (KB), breast (MCF-7) and gastric (MGC-803), during the comparison with 5-Fluorouracil as a standard drug, shown in Table2.…”