Synthesis and Biological Evaluation of Quinazolonethiazoles as New Potential Conquerors towards Pseudomonas Aeruginosa

Abstract

Novel quinazolonthiazoles were designed and synthesized as new potential antimicrobial agents by facile multi-step procedure from o-aminobenzoic acids and 2-acetylthiazole. A series of biological evaluation showed that compound 7d was the most effective quinazolonethiazole with superior activity to reference drugs chloramphenicol and norfloxacin. This active molecule displayed unobvious bacterial resistance against P. aeruginosa, the low toxicity to normal hepatocytes, suitable pharmacokinetics and drug-likeness. The preliminary biological interaction suggested that quinazolonethiazole 7d might induce bacterial death by disturbing the membrane permeability, whilst preventing bacteria from growth by integrating into DNA and binding with topoisomerase IV. These findings provided significant background for the further development of quinazolonethiazoles as new potential drugs in combating drug-resistant pathogens.

Identification of Unique Quinazolone Thiazoles as Novel Structural Scaffolds for Potential Gram-Negative Bacterial Conquerors

“…Heteroaromatic thiazole, as a member of the current research mainstream azoles, gains wide appreciations and cultivations in drug design and development due to the character of abundant electrons, which empowers it to engage with functional targets for improving biological activity. − Naturally, thiazole provides enormous contributions to successful development of clinical antibiotics such as the third and fourth cephalosporins. , Consequently, to confront drug-resistant infections, recent numerous studies endeavored to incorporate it with the antibacterial nucleus like quinolone, , sulfanilamide, , and berberine , for discovery of novel antimicrobials, among which some availably perturbed essential cellular behavior of microorganisms, holding meaningful exploring potential. Moreover, our previous research revealed that quinazolone thiazoles delivered promising antibacterial effects and low bacterial resistance . This valuable information inspires our tremendous enthusiasm to continue the system of quinazolone thiazole with different linkers to access more outstanding candidates against pathogens.…”

“…Intermediates (2−3, 10, and 12−13) were obtained according to the synthetic methods reported in the literature. 27 Z-7-Chloro-3-(3-oxo-3-(thiazol-2-yl)-1-(thiophen-2-yl)prop-1-en-2-yl)quinazolin-4(3H)-one (4a). Quinazolonthiazole 3 (200 mg, 0.65 mmol) and piperidine were stirred in ethanol at 65 °C for 0.5 h, and then, 2-thiophenaldehyde (88 mg, 0.78 mmol) was added to continue the reaction for 20 h. The resulting mixture was cooled to room temperature and purified by silica gel column chromatography (eluent, dichloromethane/petroleum ether, 1/1, v/v) to access yellow solid 4a (224 mg).…”

“…Moreover, our previous research revealed that quinazolone thiazoles delivered promising antibacterial effects and low bacterial resistance. 27 This valuable information inspires our tremendous enthusiasm to continue the system of quinazolone thiazole with different linkers to access more outstanding candidates against pathogens.…”

“…52,53 We have authenticated that quinazolone with a similar structure to 5j could effectually bind with DNA in previous work. 27 Thus, calf thymus DNA is employed to explore the binding behavior with molecule 5j for mechanistic investigation.…”

“…As a carrier of genetic information on which organisms depend for survival and reproduction, DNA has become a famous and well-explored target for the establishment of effective drugs. , We have authenticated that quinazolone with a similar structure to 5j could effectually bind with DNA in previous work . Thus, calf thymus DNA is employed to explore the binding behavior with molecule 5j for mechanistic investigation.…”