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The most important benzazole representatives, benzimidazole and benzothiazole derivatives, have been well established as principal structural motifs in medicinal and pharmaceutical chemistry. Acrylonitriles bearing heteroaromatic or aromatic moieties have been recognized as promising biologically active compounds possessing a wide range of biological activities like anticancer, antituberculostatic, antibacterial or antioxidative effects. In this paper, we report the synthesis of novel biologically active methoxy and hydroxy substituted benzimidazole and benzothiazole derivatives, related to 2, 3- disubstituted acrylonitriles. Novel compounds were prepared by classical reactions of organic chemistry and by microwave assisted reactions. Acrylonitrile derivatives bearing benzimidazole nuclei were prepared by aldol condensation of N- substituted 2-cyanomethylbenzimidazoles with corresponding hydroxy subsituted benzaldehydes in moderate to good yields. Acrylonitrile derivatives bearing benzothiazole nuclei were prepared by condensation of 2-benzothiazoleacetonitrile with corresponding methoxy and hydroxy substituted benzaldehydes. All newly prepared compounds will be screened for their antioxidant capacity using several spectroscopic methods as well as antiproliferative activity on several human cancer cells in vitro.

Cancer is a complex, prevalent and fatal disease that notably affects almost every tissue in the human body, and many anticancer drugs are currently being used clinically for the treatment of several malignancies. [1] However, solid tumors such as breast cancer, resist most of the clinically-available anticancer agents probably due to gene mutations or epigenetic modifications during the course of therapy that affect the uptake, metabolism of efflux of drugs from cancer cells. Benzoxazoles derivatives show significant pharmacophoric behavior with diverse range of biological activities including antitumor activity. [2, 3] In this paper, we present the synthesis of novel 1, 2, 3-triazolyl benzoxazole derivatives by using click reaction in deep eutectic solvents (DES). The key precursors of Schiff bases were synthesized by ultrasound irradiation, and subsequent cyclization reaction with NaCN gave the corresponding 2-arlybenzoxazoles which are furthermore converted to O-propargylated benzoxazole derivatives by microwave assisted alkylation reactions. 1, 2, 3-triazolyl benzoxazole derivatives were prepared by click-reaction of O-propargylated benzoxazole derivatives with corresponding azides in DES (ChCl/glycerol). All synthesized compounds were evaluated against Gram-positive and Gram-negative bacterial strains as well as malignant tumor cell lines. 2-(4-(2-morpholinoethoxy)phenyl)benzoxazole showed the most pronounced activity against non-small-cell lung cancer cell lines (NCI-H460, IC50=0.4 µM).

The low survivability associated with lung cancer is a clear indication of the need for more effective drugs, particularly those that act on targets or pathways of greater relevance to the disease [1]. Benzoxazole is a privileged scaffold that represents a promising class of heterocycles and the backbone of many bioactive compounds and possess antitumor activity. In recent times, much progress has been made to develop benzoxazole derivatives into clinical candidates. The growing importance of benzoxazole derivatives as therapetuic anticancer agents has fuelled the development of benzoxazole based drugs. Trends in environmentally friendly and sustainable process development during past years are abridged involving the use of alternative organic synthesis including mechanochemistry, ultrasound or microwave irradiation and greener organic solvents. Conventional organic solvents are not only hazardous to the environment but also show acute and chronic toxicity, carcinogenicity, ecological toxicity and nonbiodegradability. Deep eutectic solvents (DES) have emerged as an interesting type of ionic liquid and have proven useful as an environmentally benign sustainable alternative to the conventional organic solvents in synthetic chemistry to increase the efficiency of organic transformations. Herein we present the synthesis of novel benzoxazole derivatives substituted at position 2 with disubstituted phenyl moiety by using mechanochemical and microwave reactions as well as application of different DES, and their cytostatic and antibacterial evaluations. 4-O-alkylated benzaldehydes, as key precursors for the synthesis of target benzoxazole derivatives, were prepared in DES (ChCl/glycerol) with K2CO3 as a base and subsequent mechanochemical reactions with 2-aminophenole were afforded corresponding Schiff bases. Microwave assisted cyclization reaction of Schiff bases with NaCN in ethanol gave target 2-(3, 4-disubstitutedphenyl)benzoxazole derivatives. The novel benzoxazole derivatives were evaluated against tumor cell lines (Capan-1, NCI- H460, DND-41, K- 562, Z-138) and on the growth of grampositive and gram-negative bacterial strains. Of all tested compounds benzoxazole derivatives with 4- (N, N-diethylethoxy)phenyl substituent showed the most pronounced activity against lung carcinoma cell lines (NCI-H460, IC50=0.4-1.4 μM), while 2-(4-(2- morpholinoethoxy)phenyl)benzoxazole showed considerable activities against pancreatic adenocarcinoma (Capan-1, IC50=2 μM), colorectal carcinoma (HCT-116, IC50=5.7 μM), glioblastoma (Ln229, IC50=2.2 μM) and lung carcionoma (NCI-H460, IC50=1.3 μM) cell lines.

Cancer is one of the main causes of death worldwide along with cardiovascular diseases. Due to its high mortality rate and frequency, medicinal chemists are rapidly developing new, potent antitumor agents. Benzoxazoles are structural isosters of natural nucleotides and represent an important class of heterocyclic compounds exhibiting exceptional pharmacological activities such as anticancer, anti-inflammatory and antiviral. In addition, some of them have found application as fluorescent whitening agents and functional materials [1-2]. Utilizing conventional and green synthetic methods, novel derivatives of benzoxazole containing 1, 2, 3-triazole ring as a linker were prepared. Propargylated 2-aminobenzoxazole and 2-thiobenzoxazole were prepared in a two-step reaction including cyclization reaction of 2-aminophenol using di(imidazole-1-yl)methanimine or carbon disulfide, and subsequent N-alkylation reaction with propargyl bromide as an alkylating reagent. 2-amino- and 2-thiobenzoxazole derivatives with 1, 2, 3-triazole moiety were synthesized by Cu(I) catalyzed click reaction of 2-propargylated benzoxazole derivatives with corresponding azides. The most potent activity against acute lymphoblastic leukemia (DND-41, IC50= 1 μM) showed benzoxazole derivative consisting of coumarin ring linked via 1, 2, 3-triazole. [1] C. P. Kaushik, M. Chahal, .J. Chem. Sci. 132 (2020) 142. [2] M. Kale, V. Chavan, Mini-Rev. Org. Chem. 16 (2019) 111

The field of drug discovery is constantly advancing in its quest to find new biologically active compounds. Recently, an emerging trend in medical chemistry is molecular hybridization, which is often used as a key strategy in drug design [1]. It includes combining known biologically active moieties as scaffolds to build a new molecule that could retain properties, or potentially have new activity. Coumarin and quinoline are widely used in pharmaceuticals, as well as in new molecular hybrids. Triazole ring are also important linkage, building block and pharmachophore in molecular hybrids with quinolines and coumarins [2, 3]. In this work, we present synthesis of novel hybrids of quinoline and coumarin bridged with 1, 2, 3-triazole ring. The methylazido coumarins were prepared by cyclization of corresponding phenols and ethyl 4-chloroacetoacetate, followed by azidation. The hybrids bridged with 1, 2, 3-triazole (1-35) were prepared using Cu-catalyzed Huisgen-1, 3-dipolar cycloaddition reaction. Antitumor activity of novel molecular hybrids was examined against human tumor cell lines: glioblastoma, pancreatic adenocarcinoma, colorectal carcinoma, lung carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia and non-Hodgkin lymphoma. [1] G. Bérubé, Expert Opin. Drug Discov. 11 (2016) 281–305. [2] R. Reddyrajula. U. Dalimba, Chem. Select 4 (2019) 2685–2693. [3] K. Bhagat et. al., ACS Omega 4 (2019) 8720–8730

Benzimidazol je važan farmakofor i smatra se povlaštenom strukturom u medicinskoj kemiji.1 Derivati benzimidazola pokazuju brojne farmakološke aktivnosti poput antituberkulostatske, antimalarijske, antimikrobne, antivirusne, antitumorske i protuupalne.2 1, 2, 3-triazolni prsten kao dušiikov heterociklički gradivni blok ima značajnu ulogu u dizajnu i sintezi lijekova budući da ne predstavlja samo pasivnu poveznicu. nego je i farmakofor jer se lako povezuje s biološkim metama putem vodikovih veza i dipolnih interakcija.3 U ovom radu je prikazana sinteza i biološka ispitivanja novih derivata 2- arilbenzimidazola premoštenih 1, 2, 3-triazolnim prstenom. Ultrazvukom potpomognutom reakcijom ciklizacije O- alkiliranih benzaldehida s različito supstituiranim 1, 2-diaminobenzenom sintetizirani su 2-arilbenzimidazoli. 1, 2, 3-triazolni derivati benzimidazola pripravljeni su Huisgenovom 1, 3- dipolarnom cikloadicijom s odgovarajućim azidima. Antitumorska ispitivanja derivata benzimidazola su pokazala da derivat 2-arilbenzimidazola s N, N- dietilnim supstituentom ima najizraženiju antitumorsku aktivnost protiv tumorskih staničnih linija porijeklom iz čovjeka: adenokarcinom gušterače (Capan-1, IC50=2, 2 μM), karcinom pluća (NCI-H46, IC50=2, 2 μM), akutna limfoblastična leukemija (DND-41, IC50=2, 6 μM), kronična mijeloična leukemija (K-562, IC50=2, 0 μM) i non- Hodgkinov limfom (Z-138, IC50= 2, 0 μM). Ispitano je i antibakterijsko djelovanje novopripravljenih spojeva na bakterijskim stanicama Escherichia coli, Enterococcus Faecalis, Klebsiella Pneumonia, Pseudomonas aeruginosa, Staphylococcus aureus. Najizraženiju inhibiciju (MIC> 88-98%) je pokazao 6-klor-benzimidazolni derivat s morfolinskim supstituentom na bakteriju Enterococcus Faecalis pri svim ispitanim koncetracijama (256-0, 25 mg/L).

Benzimidazole is an important pharmacophore and represents a privileged structure in medicinal chemistry.[1] Its derivatives show numerous pharmacological activities such as antituberculostatic, antimalarial, antimicrobial, antiviral, antitumor and anti- inflammatory.[2] The 1, 2, 3-triazole products are more than passive linkers, they readily associate with biological targets, through hydrogen-bonding and dipole interactions and attract a lot of attention as pharmacophores.[3] In this paper, we present ultrasonic and microwave cyclization reaction of O-alkylated benzaldehydes with variously substituted 1, 2-diaminobenzene which gave 2- arylbenzimidazole derivatives. 1, 2, 3-triazolyl benzimidazole derivatives were prepared by Huisgen 1, 3-dipolar cycloaddition reaction using copper(II) acetate as catalyst. Antitumoral evaluations of all tested compounds revealed that the 2-arylbenzimidazole derivative with N, N- diethyl substituent showed the most pronounced activity against antitumor cell lines: pancreatic adenocarcinoma (Capan-1, IC50=2.2 μM), lung carcinoma (NCI-H460, IC50=2.2 μM), acute lymphoblastic leukemia (DND-41, IC50=2.6 μM), chronic myeloid leukemia (K- 562, IC50=2.0 μM) and non-Hodgkin lymphoma (Z-138, IC50=2.0 μM).

Cancer is the result of unwanted transformations of normal cells into tumor cells that can spread uncontrollably. It is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. The most common types of cancer in 2020. were: breast (2, 26 million cases), lung (2, 21 million cases), colon (1, 93 million cases) and prostate cancer (1, 41 million cases). Because of its frequency and high mortality rate, there is an increased demand to develop new, potent antitumor agents. Benzoxazoles represent an important class of heterocyclic compounds that exhibit a variety of pharmacological activities such as anticancer, antibacterial, antiviral, antifungal, anti-inflammatory and more. [1-3] In order to evaluate their antitumor activity, novel benzoxazole derivatives with 1, 2, 3-triazole ring as a linker were prepared by conventional and green synthetic methods. Bezoxazole derivative linked with coumarin ring through 1, 2, 3-triazole showed the most potent activity against acute lymphoblastic leukemia (DND-41, IC50= 1 μM). [1] C. P. Kaushik, M. Chahal, .J. Chem. Sci, . 2020, 132:142 [2] U. Kamal, N. M. Javed, K. Arun, Asian J. Pharm. Clin. Res., 2020, 13, 1-14 [3] R. Sattar, R. Mukhtar, M. Atif, M. Hasnain, A. Irfan, J. Het. Chem., 2020, 57, 2079-2107

The benzimidazole scaffold, as a small nitrogen-containing heterocycle, has become a fundamental building block widely incorporated in the structure of numerous synthetic molecules. Due to the fact that benzimidazole nucleus is a bioisoster of the naturally occurring purine, its derivatives may interact with different biomolecules and achieve many biological effects, of which the most important is their promising and strong antiproliferative activity [1]. In this work, the novel N- substituted-2- benzimidazolyl acrylonitriles were synthesized and tested for the antiproliferative activity in vitro on eight human cancer cell lines and one reference non- cancerous assay. Of all evaluated derivatives, the N, N-dimethylamino substituted acrylonitriles bearing N-isobutyl and cyano moieties showed the strongest and the most selective antitumor activity in the submicromolar range of inhibitory concentrations, while being significantly less toxic than the reference systems docetaxel and staurosporine. Further mechanistic studies demonstrated that the most active derivatives inhibit cancer cell proliferation by disintegration of the microtubule network, comparable with the effect of the microtubule destabilizing compounds vincristine and colchicine. With the aim of obtaining a deeper insight into the binding of the tested molecules, we employed docking simulations and quantum- chemical calculations using the SwissDock web server and the Gaussian 16 software. Computational analysis confirmed the suitability of the employed benzimidazole- acrylonitrile skeleton for the binding within the colchicine binding site in tubulin, thus rationalizing the observed antitumor activity. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached N, N-dimethylamino group as the most dominant in promoting the binding, which allows ligands to optimize favorable cation∙∙∙π and hydrogen bonding interactions with Lys352. This initial research represents a valuable foundation for the further development and the rational design of the benzimidazole-based antiproliferative substances. [1] W. Akhtar, M. Faraz Khan, G. Verma, M. Shaquiquzzaman, M. A. Rizvi, S. H. Mehdi, M. Akhter, M. Mumtaz Alam, Therapeutic evolution of benzimidazole derivatives in the last quinquennial period, Eur. J. Med. Chem. 126 (2017) 705–753. DOI: 10.1016/j.ejmech.2016.12.010