Synthesis, Antiproliferative, and Antioxidant Evaluation of 2-Pentylquinazolin-4(3H)-One(Thione) Derivatives with DFT Study
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molecules Article Synthesis, Antiproliferative, and Antioxidant Evaluation of 2-Pentylquinazolin-4(3H)-one(thione) Derivatives with DFT Study Amira A. El-Sayed 1, Mahmoud F. Ismail 1 , Abd El-Galil E. Amr 2,3,* and Ahmed M. Naglah 2,4 1 Department of Chemistry, Faculty of Science, Ain Shams University, 11566 Abbassia, Cairo 11566, Egypt; [email protected] (A.A.E.-S.); [email protected] (M.F.I.) 2 Pharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; [email protected] 3 Applied Organic Chemistry Department, National Research Center, Cairo, Dokki 12622, Egypt 4 Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre, Dokki, Cairo 12622, Egypt * Correspondence: [email protected]; Tel.: +966-543074312 Academic Editor: Qiao-Hong Chen Received: 5 October 2019; Accepted: 20 October 2019; Published: 21 October 2019 Abstract: The current study was chiefly designed to examine the antiproliferative and antioxidant activities of some novel quinazolinone(thione) derivatives 6–14. The present work focused on two main points; firstly, comparing between quinazolinone and quinazolinthione derivatives. Whereas, antiproliferative (against two cell lines namely, HepG2 and MCF-7) and antioxidant (by two methods; ABTS and DPPH) activities of the investigated compounds, the best quinazolinthione derivatives were 6 and 14, which exhibited excellent potencies comparable to quinazolinone derivatives 5 and 9, respectively. Secondly, we compared the activity of four series of Schiff bases which included the quinazolinone moiety (11a–d). In addition, the antiproliferative and antioxidant activities of the compounds with various aryl aldehyde hydrazone derivatives (11a–d) analogs were studied. The compounds exhibited potency that increased with increasing electron donating group in p-position (OH > OMe > Cl) due to extended conjugated systems. Noteworthy, most of antiproliferative and antioxidant activities results for the tested compounds are consistent with the DFT calculations. Keywords: quinazolin-4(3H)-one; quinazolin-4(3H)-thione; Schiff base; antiproliferative activity; antioxidant activity; DFT study 1. Introduction Cancer is the second leading cause of death globally, and the contribution of cancer disease to the overall mortality rate is increasing. Economically, the total annual cost of cancer in 2010 was estimated at approximately US$ 1.16 trillion [1]. So that, more rational design, synthesis, and evaluation of new compounds as anticancer, with higher efficiency is considered as urgent mission in the medicinal chemistry field. Quinazoline and quinazolinone derivatives are considered as tremendous targets for the medicinal chemists, due to the fact that they are the scaffold of different potent anticancer drugs, such as Gefitinib (trade name Iressa®), Erlotinib (trade name Tarceva®)[2–4], Methaqualone [5], Afloqualone (as anticonvulsant activity) [6,7], Chloroqualone (as antitussive), and Diproqualone (as sedative-hypnotic agents) [8] (Figure1). Molecules 2019, 24, 3787; doi:10.3390/molecules24203787 www.mdpi.com/journal/molecules Molecules 2019, 24 2 Molecules 2019, 24, 3787 2 of 19 Molecules 2019, 24 2 Figure 1. Some structures of synthetic drugs scaffold quinazoline and quinazolinone derivatives. FigureFigure 1. Some 1. Some structures structures of of synthetic synthetic drugs drugs scascaffoldffold quinazoline quinazoline and and quinazolinone quinazolinone derivatives. derivatives. In the last decades and until now, various compounds including quinazolinone moiety In the last decades and until now, various compounds including quinazolinone moiety conspicuouslyIn the last exhibited decades broad and spectrum until now, in variousnumerous compounds pharmacological including activities quinazolinone such as anticancer moiety conspicuously exhibited broad spectrum in numerous pharmacological activities such as anticancer conspicuously[9–14], anticonvulsants exhibited [15], broad antiproliferative spectrum in[16], numerous anti‐inflammatory pharmacological [17], antihypertensive activities such [18], as [9–14],[9–14], anticonvulsants anticonvulsants [15], [15], antiproliferative antiproliferative [16],[16], antianti‐‐inflammatoryinflammatory [17], [17], antihypertensive antihypertensive [18], [18], anticancer [9–14], anticonvulsants [15], antiproliferative [16], anti-inflammatory [17], antifungalantifungal [19], [19], antibacterial, antibacterial, antioxidant antioxidant [20], [20], antimicrobialantimicrobial [21], [21], anti anti‐allergic‐allergic [22], [22], antimalarial antimalarial [23], [23], antihypertensive [18], antifungal [19], antibacterial, antioxidant [20 ], antimicrobial [21], anti-allergic [22], antileishmanialantileishmanial [24], [24], and and treatment treatment of of Alzheimer’s Alzheimer’s disease (AD) (AD) [25]. [25]. antimalarialGenerally,Generally, [23 ],the antileishmanial thenatural natural products products [24], andare are treatment consideredconsidered of as Alzheimer’sas oneone of of the the diseasemost most interesting (AD) interesting [25 ].sources sources of of biologicallyGenerally,biologically active the active naturalcompounds. compounds. products Among Among are considered them, them, naturallynaturally as one occurringoccurring of the most quinazolin quinazolin interesting‐4(3‐4(3H sources)‐oneH)‐ onederivatives, of derivatives, biologically activewhichwhich compounds.can canbe isolatedbe isolated Among from from them,various various naturally plants plants andand occurring microorganisms quinazolin-4(3 such such asH )-oneasLuotonin Luotonin derivatives, A (sources;A (sources; which canPeganum bePeganum isolated nigellastrum nigellastrum from various) )[26],[26], plants 2‐2(heptan‐(heptan and microorganisms‐3‐3‐‐yl)quinazolinoneyl)quinazolinone such (sources;(sources; as Luotonin BacillusBacillus A (sources;cereus cereus) [27],Peganum) [27], Dictyoquinazol A (sources; Dictyophora indusiata) [28], and Echinozolinone (sources; Echinops nigellastrumDictyoquinazol)[26 ],A 2-(heptan-3-yl)quinazolinone (sources; Dictyophora indusiata (sources;) [28],Bacillus and cereus Echinozolinone)[27], Dictyoquinazol (sources; A Echinops (sources; echinatus) [29] (Figure 2). Dictyophoraechinatus) [29] indusiata (Figure)[ 2).28 ], and Echinozolinone (sources; Echinops echinatus)[29] (Figure2). Figure 2. Some structures of naturally occurring quinazolin‐4(3H)‐one derivatives. Figure 2. Some structures of naturally occurring quinazolin quinazolin-4(3‐4(3H)-one)‐one derivatives. Quinazolinones have been synthesized by different methodologies [28,30–37], in the present study, the conventional methodology to construct novel qunizolinone compounds has been Quinazolinones have been synthesized by different different methodologies [28,30–37], [28,30–37], in the present Quinazolinonesadopted, followed have by thebeen study synthesized of the antiproliferative by different methodologiesactivity, antioxidant [28,30–37], activity, inand the DFT present study, thethe conventional conventional methodology methodology to constructto construct novel novel qunizolinone qunizolinone compounds compounds has been has adopted, been study,calculations the conventional for the synthesized methodology compounds. to construct novel qunizolinone compounds has been followedadopted, byfollowed the study by of the the antiproliferativestudy of the antiproliferative activity, antioxidant activity, activity, antioxidant and DFT calculationsactivity, and for DFT the synthesizedcalculations2. Results compounds.for and the Discussion synthesized compounds. 2. Results 2.1. Chemistry and Discussion 2.1. ChemistryIn this interesting work, curing of anthranilic acid 1 with hexanoyl chloride 2 in dry pyridine 2.1. Chemistryafforded the corresponding N‐hexanoyl derivative 3 [38], which was cyclized by heating in distilled Inacetic this anhydride interesting to give work, 2‐pentyl curing‐4H of‐benzo[ anthranilicd][1,3]oxazin acid ‐14‐withone 4 hexanoyl[39,40] (Scheme chloride 1). 2 in dry pyridine In this interesting work, curing of anthranilic acid 1 with hexanoyl chloride 2 in dry pyridine afforded the corresponding N-hexanoyl derivative 3 [38], which was cyclized by heating in distilled afforded the corresponding N‐hexanoyl derivative 3 [38], which was cyclized by heating in distilled acetic anhydride to give 2-pentyl-4H-benzo[d][1,3]oxazin-4-one 4 [39,40] (Scheme1). acetic anhydride to give 2‐pentyl‐4H‐benzo[d][1,3]oxazin‐4‐one 4 [39,40] (Scheme 1). Scheme 1. The strategy for synthesis of compound 4. Scheme 1. The strategy for synthesis of compound 4.4. Molecules 2019, 24, 3787 3 of 19 Molecules 2019, 24 3 Benzoxazinone derivative derivative 44 waswas utilized in in situ as a precursor to construct new quinazolinone derivatives. For For instance, instance, reaction reaction of of benzoxazinone benzoxazinone derivative derivative 44 withwith formamide formamide afforded afforded 1 22-pentylquinazolin-4(3‐pentylquinazolin‐4(3HH))-one‐one 55 [41][41 ](Scheme (Scheme 2).2). The The 1H NMRH NMR spectrum spectrum of 5 exhibited of 5 exhibited a singlet a singlet peak atpeak 12.13 at 12.13 ppm ppm exchangeable exchangeable with with D2O D corresponding2O corresponding to NH to NH proton, proton, two two doublet doublet and and two two triplet peaks in the aromatic region at 8.05–7.42 ppm corresponding to four aromatic protons, and four characteristic peaks upfield upfield at 2.56–0.84 ppm for n-pentyl‐pentyl protons. Afterwards, sulfurationsulfuration