Imidazobenzothiazoles: synthesis and application

This review article focuses on the synthesis of various types of imidazobenzothiazoles, which are potentially useful for the development of biologically active heterocycles. The synthetic methods are simple and practical and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur. Also, some commercial applications of these compounds are reported as well.     

噻唑并[3,2-b][1,2,4]三唑酮衍生物的合成及抗癌活性研究

以3,4,5-三甲氧基苯甲酸为原料,经过Claisen缩合等反应设计合成一系列新的噻唑并[3,2-b][1,2,4]三唑-6-酮稠杂环衍生物并测定其体外抗肿瘤活性。目标化合物经~1HNMR、~(13)CNMR和高分辨质谱等表征后,在He La、HCT116、BEL-7402及L-02细胞中用MTT法测定其抑制细胞增殖的程度,并初步判断化合物的体外抗癌活性。结果表明,与临床常用药顺铂(DDP)相比,多数化合物具有抑制肿瘤细胞增殖活性。其中,5-(4-苄氧基苯亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮、5-(4-乙酰氧基苯亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮、5-(α-呋喃亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮和5-(α-噻吩亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮对HCT116等3种癌细胞的抑制率高于正常细胞L-02,且对癌细胞有选择性抑制作用,而对正常细胞无毒性,具有良好的后续研究价值。5-(4-氟苯亚甲基)-2-(3,4,5-三羟苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮对BEL-7402等细胞的抑制率有大幅度提高,但对L-02正常细胞的毒性更大。     

Chemistry of 2-cyanomethylene-4-thiazolidinone

This article is a brief review about the synthesis and chemistry of 2-cyanomethylene-4-thiazolidinone 1. The most significant applications of 4-thiazolidinone 1 in heterocyclic synthesis are due to its two reactive methylenes. The endo-cyclic methylene protons are activated by the neighboring carbonyl moiety and the exo-cyclic methylene protons by the adjacent cyano group. Different types of reactions, such as alkylation, coupling, and Knoevenagel condensation, as well as cyclization reactions are illustrated for the synthesis of different classes of biologically important heterocyclic skeletons from this novel precursor.     

TBHP-Mediated Intermolecular Radical Coupling and Intramolecular Cyclization Cascade: Access to Furo[2,3-b]quinoxalines and Their Photophysical Study

A cascade one-pot strategy to construct 31 examples of furo-fused quinoxalines in up to 88% yields has been devised from readily accessible β-ketothioamides and quinoxalin-2-ones in open flask at room temperature under TBHP mediated conditions. Mechanistic studies revealed that the overall reactivity relies on the seamless integration of intermolecular radical coupling and intramolecular cyclization via desulfhydration of C=S bond cleavage. Generation of H₂S as the only by-product makes this process highly attractive. Furthermore, the photophysical behavior of the furo-fused quinoxalines has also been studied.     

Epipolythiodiketopiperazine Alkaloids: Total Syntheses and Biological Activities

Epipolythiodiketopiperazine (ETP) alkaloids are structurally characterized by the presence of diketopiperazine rings having sensitive (poly)sulfide bridges, and most of them are classified as fungal secondary metabolites. Various biological activities have been reported for members of this family, including cytotoxic, antibacterial, antimicrobial, antiviral, antitumor, antiallergic, and antimalarial activities. Notably, some of the molecules were reported to show specific inhibitory activities against certain critical enzymes. Since the supply of these compounds from natural sources is quite limited, efficient chemical syntheses of ETP alkaloids would be useful for biological studies. However, total syntheses of ETP alkaloids remain a formidable challenge in current synthetic organic chemistry because of their structural complexity. In this review article, we present an overview of synthetic approaches to the ETP alkaloids during the past 50 years, and discuss significant milestones. We also summarize the biological activities of these compounds, focusing on the molecular mechanisms.     

Reaction of hydrazonoyl halides 49 1: Synthesis and antimicrobial activity of some new pyrimido[1,2-b][1,2,4,5]tetrazin-6-one,tetrazino[3,2-b]quinazolin-5-one,pyrimidino[1,2-b]1,2,4,5-tetrazin-5-one and triazolo[4,3-a]pyrimidine derivatives

Pyrimido[1,2-b][1,2,4,5]tetrazin-6-one, tetrazino[3,2-b]quinazolin-5-one, pyrimidino[1,2-b]1,2,4,5-tetrazin-5-one and triazolo[4,3-a]pyrimidine derivatives were synthesized from C-(4-methyl-2-phenyl)thiazol-5-oyl-N-phenyl-hydrazonoyl bromide and different pyrimidine-2-thiones. New compounds had their structures confirmed by elemental and spectral analysis and were screened antimicrobial activity.     

COMPARATIVE METABOLISM OF PHENANTHRO[3,4-B]THIOPHENE,PHENANTHRO[4,3-B]THIOPHENE AND THEIR CARBON ANALOG BENZO[C]PHENANTHRENE BY RAT LIVER MICROSOMES

Phenanthro[3,4-b]thiophene (P[3,4-b]T) and phenanthro[4,3-b]thiophene (P[4,3-b]T) are thiasters of weakly mutagenic benzo[c]phenanthrene (B[c]P). These polycyclic sulfur heterocycles (thia-PAHs) represent a group of chemicals which have been identified in cigarette smoke. P[3,4-b]T is a potent mutagen in Salmonella typhimurium strain TA100 in the presence of rat liver S9, whereas its isosteric isomer P[4,3-b]T is a nonmutagenic compound. In order to understand the mechanism underlying the differences in the mutagenic activity of P[3,4-b]T and P[4,3-b]T, we have investigated the metabolism of P[3,4-b]T, P[4,3-b]T, and their carbon analogue B[c]P by rat liver microsomes. The liver microsomes from rats treated with Aroclor 1254 metabolized P[3,4-b]T, P[3,4-b]T, and B[c]P at a rate nearly 7- to 9-fold greater than of the control liver microsomes. High-performance liquid chromatography (HPLC) analysis of the metabolites formed showed that B[c]P was metabolized almost exclusively to its dihydrodiols which comprised predominantly K-region diol as noted in the previous studies. Our preliminary studies on the metabolism of P[3,4-b]T, P[4,3-b]T and B[c]P by liver microsomes from control and Aroclor 1254-treated rats have shown a significant reduction in the formation of 6,7-diol (K-region diol) and 8,9-diol (diol with a bay-region double bond) of the two thia-PAHs compared to the formation of analogous 5,6-diol (K-region diol) and 3,4-diol (diol with a bay-region double bond) from B[c]P. Both P[3,4-b]T and P[4,3b]T produced a major, relatively nonpolar metabolite(s) (80–96% of total metabolites). These studies indicate that the highly mutagenic P[3,4-b]T is not metabolized to dihydrodiol with a bay-region double bond to any greater extent than the weakly or nonmutagenic B[c]P or P[4,3-b]T, suggesting that the metabolite(s) other than P[3,4-b]T8,9-diol is likely to be involved in the mutagenicity of P[3,4-b]T.     

Synthetic access to imidazo[2,1-b]thiazoles

The current review article represents a survey covering the synthetic strategies leading to imidazo[2,1-b]thiazoles since 1980. The review is classified according to nature of starting precursor either 2-aminothiazoles or 2-mercaptothiazoles.     

Synthesis of some new 3-mercapto-5-substituted-1,2,4-triazine-s-triazoles for evaluation as antimicrobial agents

The synthesis of several S- and N-substituted derivatives of 5-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-s-triazole-3-thiol, 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)-oxymethyl]-5,6-dihydrothiazolo-[3,2-b]-s-briazole, 2-[(5,6-diphenyl-1, 2,4-triazin-3-yl)oxymethyl]-5H,6,7-dihydro-s-triazolo-[3,2-b]-1,3-thiazine, 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-5,6-dihydrothiazolo-[3,2-b]-s-triazol-5-one and 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-6-phenylthiazolo-[3,2-b]-s-triazole is reported. All the novel compounds have been screened for antimicrobial activity and one of them showed noteworthy activity.     

Synthesis of Highly Substituted Imidazo[1,5‐a]quinoxalines Through a Multicomponent Reaction Followed by Deprotection–Cyclization

An operationally simple and efficient, one‐pot, two‐step methodology has been developed for the assembly of medicinally important imidazo[1,5‐a]quinoxalines. The protocol involves the multicomponent reaction of aryl aldehydes, ortho‐N‐Boc‐phenylenediamines and azidochalcones in the presence of erbium triflate as a Lewis acid catalyst, followed by deprotection–cyclization with 10% trifluoroacetic acid, furnishing the desired compounds in moderate to good yields. By virtue of their convergence, two aromatic rings and four new bonds are generated during the course of this reaction protocol. The structure of one of the compounds was proved by X‐ray crystallography.

     

Thiazolopyrimidines without bridge-head nitrogen: thiazolo [4,5-d] pyrimidines

This review article is an attempt to cover a literature survey about thiazolopyrimidine ring system without the bridge-head nitrogen: thiazolo[4,5-d]pyrimidines, preparation of the ring system via azines, azoles and other miscellaneous approaches, reactions, biological activity, application and spectroscopic and crystal X-ray determinations.     

Two-component,one-pot synthesis of pyrimido[1,2-b] [1,2,4,5]tetrazines

Derivatives containing the cyclohepta4′,5′thieno[2′,3′:4,5]pyrimido[1,2-b][1,2,4,5]-tetrazin-6-one system were prepared from the reaction of 3-amino-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (5) or its 2-methylthio derivative 6 with hydrazonoyl chlorides 9. The mechanism of the studied reactions has been discussed and the biological activity of the isolated products has been evaluated.     

Synthesis of Acenaphtho[3, 4-b]thiophene: An Aceanthrylene Isoster

The synthesis of a novel thiophene isoster of aceanthrylene is reported. The sequence involves, a newly observed regiospecific condensation of oxalylchloride to naphtho[2,3-b]thiophene. Reduction of the quinone and dehydrogenation gave the title compound in 28% overall yield. The proton nmr signals of the title compounds were assigned on the basis of COSY and NOE difference spectroscopy. Its isolectronic nature with aceanthrylene is seen in the similarity of the UV spectra.     

SYNTHESIS OF DIHYDRODIOLS OF PHENANTHRO[3,4-b]THIOPHENE AND PHENANTHRO[4,3-b]THIOPHENE

A number of sulfur analogs of polynuclear aromatic hydrocarbons (thia-PAHs) have been identified in cigarette smoke condensate. Phenanthro[3,4-b]thiophene (P[3,4-b]T) and phenanthro[4,3-b]thiophene (P[4,3-b]T) are sulfur analogs of benzo[c]phenanthrene, which is known to be metabolized to one of the most tumorigenic fjord region diol epoxides tested thus far. Although fjord region diol epoxides of P[3,4-b]T and P[4,3-b]T are expected to be potent mutagens and tumorigens, these two thia-PAHs differ greatly in their mutagenic potencies. In contrast to P[3,4-b]T which is as mutagenic as benzo[a]pyrene, its isoster P[4,3-b]T is a nonmutagenic compound. In order to understand the basis underlying the difference in the mutagenic potency of P[3,4-b]T and P[4,3-b]T, we require these thia-PAHs and their dihydrodiol derivatives for investigating their metabolism and mutagenic/carcinogenic activity. In these studies, we have investigated the Suzuki cross-coupling reaction for an abbreviated synthesis of P[3,4-b]T, P[4,3-b]T, and their dihydrodiol derivatives from easily available reagents.     

2-Mercapto-4,6-disubstituted nicotinonitriles: versatile precursors for novel mono- and bis[thienopyridines]

A series of novel thieno[2,3-b]pyridines were prepared from the reaction of the appropriate bromoacetylbenzofurans or bromoacetylbenzothiazole with the corresponding pyridinethione derivatives in ethanolic sodium ethoxide at reflux. Moreover, new bis(thieno[2,3-b]pyridine) derivatives have also been synthesized by the reaction of the appropriate bis-bromoacetyl derivatives with the corresponding pyridinethiones in the presence of sodium ethoxide. Attempts to synthesize the target bis(thieno[2,3-b]pyridine) derivatives by bis-alkylation of the corresponding (thieno[2,3-b]pyridin-2-yl)(hydroxyphenyl)methanone with the appropriate dihaloalkanes using a mild base were unsuccessful.     

碱性离子液体催化“一锅法”合成吡唑[5，4-b]-γ-吡喃衍生物

在水相中以碱性离子液体[H3N＋CH2CH2OH][CH3COO-]为催化剂,芳香醛、丙二腈和4,5-二氢-3-甲基-5-氧代-1-苯基吡唑为原料一锅法反应合成一系列2-氨基-4-芳基-3-氰基-5-甲基-7-苯基吡唑[5,4-b]-γ-吡喃衍生物。该方法利用了廉价易得的离子液体为催化剂,避免使用有毒有害的有机溶剂,反应条件温和,适合工业化生产。     

6-甲基-2-苯基咪唑[2,1-b]并-1,3,4-噻二唑-5-N'-取代苯基亚甲基碳酰肼的设计与合成

根据已有的具有抗肿瘤活性的咪唑[2,1-b]并-1,3,4-噻二唑类化合物的结构及其构效关系,以2-氨基-5-苯基-1,3,4-噻二唑和溴代乙酰乙酸乙酯为原料设计并合成了8个6-甲基-2-苯基咪唑[2,1-b]并-1,3,4-噻二唑-5-碳酰肼的腙类衍生物.通过1HNMR、LC-MS、IR等方法对其结构进行了确证.     

均三唑并噻二唑类化合物研究进展

综述了均三唑并噻二唑类化合物的最新进展。陈述了均三唑并噻二唑类化合物的合成方法;由于该类化合物的各种活性主要由该化合物的结构决定,所以将本类化合物按结构分为五大类;3,6位叠加非功能化的烃基或芳香基,6位叠加杂环及含活性杂原子,6位叠加水溶性基团,3位叠加特殊基团,及多环结构。并讨论了一些合成的新方法,并进一步提出该领域研究前景及有待于解决的问题。     

A short-cut to 2,7-dihydrothiopyrano[2,3-b]pyrrole

A simple original approach to earlier unknown parent 2,7-dihydrothiopyrano[2,3-b]pyrrole (5) from allyl isothiocyanate and propargyl bromide via one-pot synthesis and thermal rearrangement of 2-(prop-2-ynylsulfanyl)-1H-pyrrole (4) has been developed. The compound 5 in the present study was successfully examined as 2,7-dihydrothiopyrano[2,3-b]pyrrole scaffold in the synthesis of corresponding N- and C-pyrrolecarbodithioates.     

咪唑并[2,1-b]噻唑衍生物的合成及生物活性进展

根据环上取代基的不同咪唑并[2,1-b]噻唑衍生物具有多种多样的生物活性。通过对咪唑并[2,1-b]噻唑衍生物合成方法的不同进行分类,综述了近年来咪唑并[2,1-b]噻唑衍生物的合成及其生物活性,结果表明在咪唑并噻唑环上引入药理活性基团会增强其生物活性。咪唑并[2,1-b]噻唑环一般由Hanzstch方法合成,近年来也出现了一些新的合成方法,如Sonogashira、Suzuki反应和金属催化芳基化,对这些新方法合成咪唑并噻唑环及其衍生物也进行了综述。