Design and Synthesis of Quinazolinone-Triazole Hybrids as Potent Anti-Tubercular Agents

Abstract

A straightforward and convenient methodology has been developed for the reaction of 2-aminobenzamide and carbonyls affording 2,3-dihydroquinazolin-4(1H)-ones using aqueous solution of [C 12 Py][FeCl 3 Br]. The developed methodology was applied for the synthesis of 25 quinazolinone-triazole hybrids followed by evaluation of their in vitro anti-tubercular (TB) activity. The results revealed that 8 quinazolinone-triazole hybrids displayed promising activity having MIC values of 0.78−12.5 μg/ mL. The compound 3if with MIC 0.78 μg/mL was found to be the lead nominee among the series, better than Ethambutol, a first line anti-TB drug and comparable with Rifampicin. The active compounds with MIC values ≤ 6.25 μg/mL were subjected to in vitro cytotoxicity and found nontoxic. In drug−drug interaction, compounds 3ia and 3ii interacted synergistically with all the three anti-TB drugs, INH, RFM, and EMB. Other 3 compounds interacted either in synergistic or additive manners. Important information on the binding interaction of the target compounds with the active sites of 1DQY Antigen 85C from Mycobacterium tuberculosis and Enoyl acyl carrier protein reductase (InhA) enzymes was obtained from molecular docking studies. Screening of the drug-likeness properties and bioactivity score indicates that synthesized molecules could be projected as potential drug candidates. Based on the current study, quinazolinone-triazole hybrids framework can be useful in drug development for TB.

Click chemistry: A fascinating, Nobel-winning method for the improvement of biological activity

“…Although synthetically derived those compounds containing 1,2,3-triazole group have various biological activities such as anticancer [41][42][43][44] , antibacterial [45,46] , antifungal [47,48] , anti-HIV [49,50] , antituberculosis [51,52] , antioxidant [53,54] , antiproliferative [55,56] and enzyme inhibitory [57,58] , these compounds are not found in nature. Therefore, the importance of these compounds in medicinal chemistry field has become undeniable, and so 1,2,3-triazole groups have been described as a "pharmacophore group" with the meaning of the main functional group responsible for the effect of a drug compound and the synthesis of the related compound has been carried out by many scientists after that time [59] .…”

Design and synthesis of γ‐Fe2O3@Ag‐S‐CH2‐COOH nanocatalyst for one‐pot synthesis of 2,3‐dihydroquinazolin‐4(1H)‐ones and their anti‐skin cancer activity

“…The quinazolinone ring is found in so many naturally occurring organic compounds, and it has furthermore shown to be a useful privileged scaffold for applications like library development and drug discovery 16,17 . There have been studies of several quinazolinone scaffolds with a wide range of biological activities, including anti‐cancer, anti‐tumor, anticonvulsant, anti‐malarial, anti‐fungal, anti‐bacterial, anti‐inflammatory, matrix metalloproteinases (MMP) inhibitors, anti‐diabetic, diuretic, anti‐tubercular, herbicidal, and plant growth regulators 18–21 . The quinazolinones can be further divided based on substitution pattern on its central ring, including 2‐substituted‐4(3 H )‐quinazolinones,3‐substituted‐4(3 H )‐quinazolinones, 2,3‐disubstituted‐4(3 H )‐quinazolinones, and 4‐substituted quinazolines 22 .…”

“…16,17 There have been studies of several quinazolinone scaffolds with a wide range of biological activities, including anticancer, anti-tumor, anticonvulsant, anti-malarial, antifungal, anti-bacterial, anti-inflammatory, matrix metalloproteinases (MMP) inhibitors, anti-diabetic, diuretic, anti-tubercular, herbicidal, and plant growth regulators. [18][19][20][21] The quinazolinones can be further divided based on substitution pattern on its central ring, including 2-substituted-4(3H)-quinazolinones,3substituted-4(3H)-quinazolinones, 2,3-disubstituted-4 (3H)-quinazolinones, and 4-substituted quinazolines. 22 Typically, 2,3-dihydroquinazolin-4(1H)-ones are synthesized by reductive cyclization of aldehydes or ketones with 2-aminobenzamide.…”

Copper‐Catalyzed Acceptorless Dehydrogenative Coupling of 2‐Aminoaryl Methanols with Nitriles for Accessing Quinazolines and Quinolines

“…Due to the high medicinal value of quinazoline derivatives, development of new synthetic strategies still seems to be an attractive field of research. There are several synthetic approaches developed for the synthesis of quinazolines, [10a–f] among them one of the most recent methods is the acceptorless dehydrogenative coupling (ADC) of 2‐aminoaryl methanols with different nitriles. A significant development has been observed in the synthesis of quinazoline derivatives using this technique.…”