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RSC Advances RSC Advances View Article Online REVIEW View Journal | View Issue Recent advances in the pharmacological diversification of quinazoline/quinazolinone Cite this: RSC Adv., 2020, 10,41353 hybrids Prashant S. Auti,† Ginson George† and Atish T. Paul ‡* Due to the pharmacological activities of quinazoline and quinazolinone scaffolds, it has aroused great interest in medicinal chemists for the development of new drugs or drug candidates. The pharmacological activities of quinazoline and its related scaffolds include anti-cancer, anti-microbial, anti-convulsant, and antihyperlipidaemia. Recently, molecular hybridization technology is used for the development of hybrid analogues with improved potency by combining two or more pharmacophores of bioactive scaffolds. The molecular hybridization of various biologically active pharmacophores with quinazoline derivatives resulted in lead compounds with multi-faceted biological activity wherein specific Received 31st July 2020 as well as multiple targets were involved. The present review summarizes the advances in lead Accepted 27th October 2020 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. compounds of quinazoline hybrids and their related heterocycles in medicinal chemistry. Moreover, the DOI: 10.1039/d0ra06642g review also helps to intensify the drug development process by providing an understanding of the rsc.li/rsc-advances potential role of these hybridized pharmacophoric features in exhibiting various pharmacological activities. 1. Introduction molecules is widely known as molecular hybridization. The molecular hybridization strategy is emerging as a novel Nowadays, “one drug one target one disease approach” is not approach, involving the conglomeration of two or more phar- appropriate in complex diseases such as cancer and infectious macophores in one scaffold to develop hybrid multi-functional 1,2 5 This article is licensed under a diseases. This conventional approach of disease treatment molecules. The presence of two or more biologically active cannot overcome the phenomenon of drug resistance. Conse- pharmacophores in one unit will synergize the biological quently, polypharmacy may prove benecial by the use of two or activity as well as increase its ability to interact with more than 6 more drugs that interact simultaneously at different targets. one biological target. Due to such properties of hybrid Open Access Article. Published on 12 November 2020. Downloaded 9/29/2021 1:01:55 AM. However, the use of multiple drug combinations is oen linked analogues, it is possible to develop combination therapies using with drug–drug interactions and altered pharmacokinetics, single multi-functional molecules. leading to severe unintended outcomes that may result in the Quinazoline is a nitrogen containing fused heterocycle, failure of the treatment. Altered pharmacokinetics and phar- having four isomeric forms, i.e., quinazoline, quinoxaline, cin- macodynamics of drugs used in combination may be due to the noline, and phthalazine, depending upon the position of the 7 induction or inhibition of hepatic enzymes, which are respon- nitrogen atom in the heterocyclic ring system. Carbonyl linkage sible for drug metabolism.1 Hence, in order to modulate more on the quinazoline ring will give rise to quinazolinone (4(3H)- than one disease target simultaneously, molecular hybrids were quinazolinone & 2(1H)-quinazolinone). designed by combining two or more known active pharmaco- Amongst all the isomeric forms, quinazoline and quinazoli- phores.3 A molecular hybrid is a combination of two or more none are medicinally important nitrogen heterocycles, displaying 8 independently acting pharmacophores that are covalently diverse biological activities including anti-microbial, anti- 9,10 11 12 13 linked. It can be achieved by the method of linking or frame- convulsant, anti-cancer, anti-malarial, anti-hypertensive, 14 15 16 work integration to form one molecule, having increased the anti-inammatory, anti-diabetic, anti-tumor, anti-cholines- 17 18 pharmacological activity.4 The strategy of designing such hybrid terase, dihydrofolate reductase inhibition, cellular phosphory- lation inhibition,19 and kinase inhibitory activities.20 There are many synthetic and natural product-based drugs, containing Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of quinazoline and quinazolinone moiety, which are used clinically Technology and Science, Pilani (BITS Pilani), Pilani Campus, Pilani, 333 031, for treating various disease conditions (Fig. 1 and 2).21 Rajasthan, India. E-mail: [email protected] Hybrid analogues containing quinazoline/quinazolinone † Equal contribution. and other biologically active pharmacophores may result in ‡ Present address: Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS Pilani), Pilani drugs with increased potency and reduced drug resistance. Campus, Pilani – 333031, Rajasthan, India. There are many reports available on the design of various This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10,41353–41392 | 41353 View Article Online RSC Advances Review Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Fig. 1 Pharmacological importance of quinazolinone-based drugs. quinazoline/quinazolinone-based hybrid analogues against based hybrids is discussed along with their pharmacological a variety of disease conditions. activities (in the areas of cancer, infectious diseases, diabetes, and In the current review, different strategies and approaches that CNS disorders) and the effect of various substituents on the were employed in the design of quinazoline/4(3H)-quinazolinone- pharmacological activity. This article is licensed under a Open Access Article. Published on 12 November 2020. Downloaded 9/29/2021 1:01:55 AM. Fig. 2 Pharmacological importance of quinazoline-based drugs. 41354 | RSC Adv.,2020,10,41353–41392 This journal is © The Royal Society of Chemistry 2020 View Article Online Review RSC Advances Scheme 1 Synthetic scheme for quinazolinone-phenylquinoxaline hybrids. 2. Anti-cancer hybrids evaluated their anti-cancer potential against 4 cancer cell lines (HeLa, MIAPACA, MDA-MB-231, and IMR32).22 Palladium (Pd)- catalyzed Heck cross coupling was utilized for the coupling of Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Cancer is a cell cycle disease, associated with uncontrolled cell division of abnormal cells. It continues to be one of the major halogenated quinoxaline with substituted 3-allylquinazoli- health problems all over the world. There are many anti-cancer nones. Two series of hybrid analogues (with alkenyl and alkyl drugs in the market but still the demand is evergreen due to linkages) were synthesized. These compounds of both the series drug resistance. Hybrid drugs with multiple mechanism of have shown signicant to moderate anti-cancer activity (GI50 ¼ action may be of great value for cancer treatment. Some of the 0.08–0.2 mM) against all the four cancer cell lines, as compared hybrid analogues based on quinazoline and quinazolinone with doxorubicin (GI50 ¼ 0.023–0.097 mM) and paclitaxel (GI50 ¼ moiety are discussed below. 0.025–0.091 mM), which were used as standards. Compound 1 Palem et al. synthesized novel hybrid analogues by the with alkenyl linker (GI50 ¼ 0.038–1.8 mM) and compound 2 with This article is licensed under a combination of quinazolinone and allylphenyl quinoxaline and alkyl linker (GI50 ¼ 0.032–1.2 mM) were most potent against Open Access Article. Published on 12 November 2020. Downloaded 9/29/2021 1:01:55 AM. Scheme 2 Synthetic scheme for sulfamide-linked quinazolinone hybrids. This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10,41353–41392 | 41355 View Article Online RSC Advances Review Creative Commons Attribution-NonCommercial 3.0 Unported Licence. This article is licensed under a Open Access Article. Published on 12 November 2020. Downloaded 9/29/2021 1:01:55 AM. Fig. 3 Designing strategy for oxazoline- and dihydroquinazolinone-based hybrids. above cell lines (Scheme 1). The designed analogues were found (GI50 in the range of 0.296–1.743 mM) as that of compound 3 to intercalate with DNA, when analyzed by docking interactions (Scheme 2). 24 with the DNA molecule (AGACGTCT)2 (PDB code: 1N37). Kamal et al. have designed hybrid analogues based on 2,3- Venkatesh et al. have designed and synthesized sulphamide- dihydro-2-aryl-4-quinazolinones (DHPQZ) and diaryl-substituted linked dihydroquinazolinone hybrids and evaluated their anti- isoxazoline/isoxazole, wherein both the scaffolds were reported cancer potential on various cancer cell lines (HeLa, MDA-MB- for tubulin polymerization inhibitory activity.25–28 Four series of 231, PANC-1, A549 (ref. 23)). Series of compounds, with or hybrid analogues were designed and synthesized by linking without aliphatic linkage, have shown signicant growth inhibi- DHPQZ and isoxazoline/isoxazole with the alkyl chain linkers of tion against all the tested cell lines with GI50 in the range of 0.045– variedchainlength(Fig.3)compound8c was found to have 6.94 mM. Amongst them, compound 3 was found to be potent potential anti-cancer activity, when tested against 18 human (GI50 in the range of 0.09–0.21 mM).Itwasfoundthatthealkyl cancer cell lines. Compound 8c was found to cause signicant linkage is also important from the activity point of view, as disruption of microtubules in MCF-7 cells along with nuclear compound 4 with propyl
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