Synthesis and Biological Evaluation of Some Novel Thiazole-Based Heterocycles As Potential Anticancer and Antimicrobial Agents
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molecules Article Synthesis and Biological Evaluation of Some Novel Thiazole-Based Heterocycles as Potential Anticancer and Antimicrobial Agents Sraa Abu-Melha 1,* , Mastoura M. Edrees 1,2,*, Heba H. Salem 3,4, Nabila A. Kheder 5,6, Sobhi M. Gomha 5,7 and Mohamad R. Abdelaziz 8 1 Department of Chemistry, Faculty of Science, King Khalid University, Abha 61413, Saudi Arabia 2 Department of Organic Chemistry, National Organization for Drug Control and Research (NODCAR), Giza 12311, Egypt 3 Faculty of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia; [email protected] 4 Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt 5 Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt; [email protected] (N.A.K.); [email protected] (S.M.G.) 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia 7 Department of Chemistry, Faculty of Science, Islamic University in Almadinah Almonawara, Almadinah Almonawara 42351, Saudi Arabia 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, MIU University, Cairo 19648, Egypt; [email protected] * Correspondence: [email protected] (S.A.-M.); [email protected] (M.M.E.); Tel.: +966-504-757-797 (S.A.-M.); +966-545-888-764 (M.M.E.) Received: 13 December 2018; Accepted: 26 January 2019; Published: 1 February 2019 Abstract: A novel series of thiazole-based heterocycles was synthesized using 1,3-dipolar cycloaddition reactions in the presence of chitosan-grafted-poly(vinylpyridine) as an eco-friendly biopolymeric basic catalyst. The molecular structure of the synthesized compounds was illustrated by spectroscopic and elemental analysis. Various in vitro biological assays were performed to explore the potential antitumor, antimicrobial and hepatoprotective activities of the newly synthesized compounds. The cytotoxic activities were assessed against human hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116) and breast cancer (MCF-7) cell lines and results revealed that all compounds displayed antitumor activities with the chlorine-containing derivatives, 11c and 6g, being the most potent. The majority of the tested thiazole derivatives exhibited satisfactory antibacterial activity towards the used gram positive and gram-negative bacterial species. Moreover, many derivatives showed weak hepatoprotective activity against CCl4-induced hepatotoxicity. Keywords: thiazoles; hydrazonoyl halides; hepatoprotective activity; anticancer activity; antimicrobial activity 1. Introduction Synthesis of novel bioactive compounds using green methods that minimize the use and generation of hazardous substances, is a major aim for many researchers. Thiazole derivatives have gained considerable attention because of their broad biological activities that include antidiabetic, antimicrobial, anti-inflammatory, anticancer, anti-Alzheimer, antihypertensive, antioxidant and hepatoprotective activities [1–16]. In addition, many thiazole-containing drugs such as Abafungin, Alagebrium, Acotiamide, Amiphenazole, Brecanavir, Cefepime, Carumonam, and Cefmatilen are commercially available. Molecules 2019, 24, 539; doi:10.3390/molecules24030539 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 14 hepatoprotective activities [1–16]. In addition, many thiazole-containing drugs such as Abafungin, Alagebrium, Acotiamide, Amiphenazole, Brecanavir, Cefepime, Carumonam, and Cefmatilen are Molecules 2019, 24, 539 2 of 15 commercially available. Cancer is regarded as one of the dominant causes of mortality nowadays. The development of new Cancerantitumor is regarded agents asrepresents one of the an dominant urgent need causes due of mortalityto the increasing nowadays. problems The development of various, of sometimes,new antitumor intolerable agents represents toxic side an effects urgent needof th duee currently to the increasing marketed problems drugs and of various, the evolution sometimes, of resistanceintolerable to toxic their side actions effects [17,18]. of the Furthermore, currently marketed liver diseases drugs are and viewed the evolution as one of of the resistance highly serious to their healthactions issues [17,18 globally]. Furthermore, [19]. The liver lack diseasesof satisfacto arery viewed treatment as one strategies of the highly for these serious diseases health with issues the occurrenceglobally [19 of]. Thedifferent lack ofside satisfactory effects upon treatment long term strategies therapy, for raise these the diseases demand with for thefinding occurrence out new of chemicaldifferent sideentities effects that upon offer longmore term efficient therapy, hepatoprotection raise the demand and forconsiderable finding out safety. new chemicalMoreover, entities there isthat a offercontinuous more efficientcompelling hepatoprotection need for the anddevelo considerablepment of new safety. antibiotics Moreover, to there replace is a the continuous current medicationscompelling needthat are for losing the development their efficacy of and new that antibiotics could have to replace higher theefficiency current or medications a wider spectrum. that are losingIn theirview efficacy of these and precedents that could haveand highertogether efficiency with our or aresearch wider spectrum. concerns of developing new convenientIn view ofapproaches these precedents for the and synthesis together withof ourdifferent research heterocyclic concerns of developingsystems with new auspicious convenient pharmacologicalapproaches for theactivities synthesis [20–25], of different we present heterocyclic in this report systems an effi withcient synthesis auspicious of pharmacologicalsome new series ofactivities novel [20thiazole–25], we derivatives present in thisusing report chitosan-grafted-poly(vinyl an efficient synthesis of some pyridine) new series as ofan novel eco-friendly thiazole biopolymericderivatives using basic chitosan-grafted-poly(vinyl catalyst. Additionally, we pyridine)have assessed as an eco-friendlya variety of biological biopolymeric activities basic catalyst.for the newlyAdditionally, synthesized we have compounds assessed a varietythat demonstrated of biological activitiestheir potential for the newlyantitumor, synthesized antimicrobial compounds and hepatoprotectivethat demonstrated effectiveness. their potential antitumor, antimicrobial and hepatoprotective effectiveness. 2. Results Results and and Discussion Discussion 2.1. Chemistry Chemistry RefluxingRefluxing of 5-acetyl-4-methyl-2-phenyl-thiazole ( (11))[ [26]26] and 2-cyanoacetohydrazide ( (22))[ [27]27] 0 afforded a single productproduct identifiedidentified asas 2-cyano-2-cyano-NN′-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)--(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)- acetohydrazide ( 3, Scheme 11).). H C O 3 N O H3C N CN O H N CN S H 2 N CH3 S H 2 N CH Ph 3 3 Ph N EtOH\dps HCl 1 NNHAr MW TEA\Dioxane or R Cl Chitosan-grafted-poly 4 (4-vinylpyridine) / Dioxane H C O 3 N N C N S H b a CH3 Ph N R N NH Ar 5 -H2O b a NC R H3C O H C N NH 3 N 2 N N N S H H N S CH3 N Ar CH3 Ar N Ph N R Ph N 7 6 6a-h RAr aCOCH3 Ph bCOCH3 4-MeC6H4 cCOCH3 4-MeOC6H4 dCOCH3 4-ClC6H4 eCOOEtPh fCOOEt4-MeC6H4 gCOOEt2,4-(Cl)2C6H3 hCONHPhPh Scheme 1.1.Synthesis Synthesis of of thiazolyl thiazolyl pyrazoles pyrazoles6a–h 6a. –h. Its mass spectrum was compatible with the molecular formula C15H14N4OS and its IR spectrum showed absorption bands at 1643, 2338, and 3430 cm−1 due to amido carbonyl group, cyano and NH functions, respectively. Also, its 1H-NMR revealed signals at δ 2.49, 2.72, 3.30 and 10.6 due to two Molecules 2019, 24, x FOR PEER REVIEW 3 of 14 Its mass spectrum was compatible with the molecular formula C15H14N4OS and its IR spectrum −1 showedMolecules absorption2019, 24, 539 bands at 1643, 2338, and 3430 cm due to amido carbonyl group, cyano and3 of NH 15 functions, respectively. Also, its 1H-NMR revealed signals at δ 2.49, 2.72, 3.30 and 10.6 due to two methyl, CH2, and NH protons, respectively. Moreover, its mass spectrum showed a molecular ion peakmethyl, at m/ CHz = 2,298.and NH protons, respectively. Moreover, its mass spectrum showed a molecular ion peakTreatment at m/z = 298.of hydrazone derivative 3 with the appropriate hydrazonoyl halides 4a–h [28–32] using Treatmenttriethylamine of hydrazone or chitosan derivative as a basic3 with catalyst the appropriate and under hydrazonoyl the same halides experimental4a–h [28 –conditions,32] using affordedtriethylamine in each or case chitosan the same as a basic products catalyst whic andh are under identified the same as experimental the thiazole conditions,derivatives afforded6a–h rather in each case the same products which are identified as the thiazole derivatives 6a–h rather than the other than the other possible product 7 based on the spectral data (IR, MS and 1H-NMR) of the isolated possible product 7 based on the spectral data (IR, MS and 1H-NMR) of the isolated products (Scheme1, products (Scheme 1, see Supporting Information). The distinction between the two possible products see Supporting Information). The distinction between the two possible products 6 and 7 was done 6 and 7 was done based on the results of the spectral analysis. The IR spectra showed the absence of based on the results of the spectral1 analysis. The IR spectra showed the absence of nitrile absorption nitrile absorption band.1 Also, their H-NMR spectra revealed the presence of signals corresponds to band. Also, their H-NMR spectra revealed the presence of signals