Synthesis and Biological Evaluation of Bis‐Imidazolidineiminothiones: A Comparative Study

Abstract

A series of 15 novel symmetrical and non-symmetrical bis-imidazolidineiminothiones (6a-g, 7a-e, 8a,b, and 9) with various substituents at N-(1) (p-tolyl, p-methoxyphenyl, p-ethoxyphenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, and 3,5-dichlorophenyl) and different linkers between the N-(3) atoms [4,4'-oxybis(4,1-phenylene), 2,2'-dimethoxybiphenyl, and (1,3,3-trimethylcyclohexyl)methyl)] were prepared in 65-75% yields from substituted N-arylcyanothioformanilides and various bis-isocyanates. Screening for cytotoxicity against the HEPG2, HEP2, MCF7, and HCT116 tumor cell lines gave IC50 values ranging from 6.3 to 84.6 µM, where compounds 6b,d,e,g and 7a were markedly active against a least one cell line, underlining the matching effect of properly positioned substituents on N-(1) and the appropriate N-(3)-N-(3) linker. Likewise, all heterocyles were tested against microbial organisms (Pseudomonas aeruginosa, Sarcina lutea, Bacillus pumilus, and Micrococcus luteus) and fungal strains (Candida albicans and Penicilium chrysogenum). Most compounds showed significant antibacterial and antifungal activities, reaching in certain cases the same level of antimicrobial activity as the standard antibacterial agent erythromycin and the antifungal agent metronidazole. The antimicrobial activity was further supported by quantitative assessment of susceptibilities of a selection of the preceding microorganisms using minimum inhibitory concentration and minimum bactericidal concentration techniques. Finally, the antiviral properties of all compounds were investigated against the viral strains HAV, HSV1, and CoxB4, where 6c,d,f and 7a,c,e were markedly active against one or two viral strains, reducing the virus plaque count of various viral strains by 66 to 88%. Structure activity relationship studies revealed several matching pairs of aromatic substituents on N-(1) and the N-(3)-N-(3) linkers, which could serve to optimize structural features for high activity to eventually render such compounds clinically useful drug agents.

Synthesis and characterization of new imidazolidineiminothione and bis-imidazolidineiminothione derivatives as potential antimicrobial agents

“…The 1 H NMR spectra of compounds 2a-c exhibited two singlet signals around δ 8.60 (C=NH) and 9.60 ppm (NH imidazole ring) along with aromatic protons. 13 C NMR spectra of compounds 2b,c displayed signals at δ 187.8-188.2 ppm due to C=S. The reaction mechanism was assumed to proceed through a nucleophilic attack of the nitrogen atom of the cyanothioformamide moiety (1a) to the cyano group in arylhydrazonomalononitrile to form intermediate that followed by intramolecular cyclization to yield the cyclized products 2 as illustrated in Scheme 1.…”

“…Also, 1 H NMR spectra showed another specific broad signal around δ 9.42 ppm for NH proton. 13 C NMR spectrum of compound 3b displayed four signals at δ 13.5, 19.3, 20.8 and 29.0 ppm for butyl carbons, three signals at δ 153.8, 154.6 and 183.1 ppm for C=N, C=O and C=S, respectively. 5-Imino-5-thioxo-2-imidazolidinone derivatives (3a-c) were furnished as the sole products, indicating that the ring closing reaction proceeds via a single path, which involves attack via the nitrogen atom.…”

“…Moreover, previous reports demonstrated that synthetic imidazoles act either as inhibitors of α-adrenoceptor mediated events in platelets [7] or inducers of platelets activation [8]. Imidazolidineiminothiones and the various heterocycles derived from them were shown to exhibit an interesting and a wide range of pharmacological effects including antitumor, antiviral, antimicrobial and antifungal strains [9][10][11][12][13][14][15]. N-Substituted cyanothioformamides were used as a key intermediate for a number of interesting heterocyclic ring closures such as imidazole [16], oxazole [17], and thiazole [18,19].…”

“…In view of the above-mentioned findings, and as a continuation of our effort to identify new candidates [9][10][11][12][13][14][15], which are crucial in designing new, potent, selective, and less toxic antimicrobial agents, its report herein the synthesis and antimicrobial evaluation of some novel imidazolidineimino thione. The target compounds were rationalized so as to comprise some pharmacophores that are believed to be responsible for the biological activity of some relevant chemotherapeutic such as the carbonyl, thiocarbonyl, imino and cyano groups functionalities.…”

N‐Arylcyanothioformamides: Preparation Methods and Application in the Synthesis of Bioactive Molecules

“…Consequently, N ‐arylcyanothioformamide reagents have found many applications in synthetic organic chemistry. The use of such reagents in heterocyclic chemistry has been nicely showcased by many researchers in the synthesis of otherwise inaccessible plethora of highly bioactive heterocyclic compounds, drug targets, and natural products such as luciferin . Although cyanothioformamides were first reported in 1904 and have been extensively used ever since, their full synthetic potential is still being established and several research groups around the globe are still aggressively pursuing such endeavour as demonstrated by the recent surge of research articles published by various groups on a wide range of transformations mediated by such reagents ( vide infra ).…”