Medicinal Chemistry

Synthesis of 3-Isopropylbenzo[D]Oxazol-2(3H)-One Amides and Urea Derivatives; Evaluation of their Anti-Mycobacterial and Cytotoxic Activity

Abstract

Indrasena Reddy K, Aruna C, Padma Sridevi J, Yogeeswari P, Sriram D and Vijayakumar V

Tuberculosis (TB) is a traditional disease caused by infection with Mycobacterium tuberculosis, it is a serious public health issue due to its risk of person-to-person transmission, and high level of morbidity and humanity. The World Health Organization (WHO) estimates 11.4 million people worldwide are infected with both Mycobacterium tuberculosis (Mtb) and HIV. Currently, there are approximately 8 million new infections and 3 million deaths attributed to M. tuberculosis annually. One of the major problems associated in comprehensive control of TB is that the restart of the disease in patients who carry a latent syndrome, in which the bacteria is in slow budding or non growing state and is refractory to treat with predictable anti-TB drugs. Directly observed treatment (DOT) is presently practicing for standard TB chemotherapy. It is well known that the resistance levels are poor in the areas with a strongly performing DOTS programmes. However, various drugs available in the market cannot be used for prolonged times due to diverse side effects. Therefore, the development of new and safe anti-TB drugs is in high demand. The major investigation on sEH inhibitors focused on urea, amide, amino- heterocycles and carbamate derivatives, but research on new compound structures is limited. Benzoxazolones are widely distributed in plants and are of increasing interest for a variety of pharmacological properties, such as detoxification, antibacterial, anti- HIV, anti-inflammatory, and transequilizers. Since benzoxazolones are active and inexpensive, many structural modification and preliminary bioactivity evaluation studies have been performed based on benzoxazol-ones. In this paper, 3-isopropyl benzo[d]oxazol-2(3H)-one amides and urea analogues were synthesized and evaluated as sEH inhibitors in vitro, and their anti-tuberculosis activities were determined in vivo. The 3-isopropylbenzo[d]oxazol- 2(3H)-one heterocycles has received considerable attention from the medicinal chemists owing to their capacity to mimic a benzamides or a phenyl urea moiety in a metabolically stable template. This class of compounds has led to the discovery of a number of derivatives endowed with antibacterial-antifungal, analgesic-antiinflammatory, anticonvulsant, dopaminergic, HIV-1 reverse transcriptase activity, and normolipenic agents. Usually functionalization of the nitrogen atom is of interest, since the electronic characteristic of this atom can be decisive for the biological activity. Nevertheless, most efforts have focused on N-, 5-, or 6-substituted benzoxazol-ones. Presently, 5-substituted benzoxazolone derivatives have been scarcely prepared, and few reports have described the sEH inhibitory activities or anti-tuberculosis activities. The pronounced biological activity of benzoxazolone derivatives and the lack of structure-bioactivity relationships prompted our investigation on 5-substituted-3- isopropylbenzo[d]oxazol-2(3H)-one.