Optimization of Thiazolidone Scaffolds Using Pocket Modeling for Development of Potential Secretory System Inhibitors of <i>Mycobacterium tuberculosis</i>

Abstract

Amaç: Mycobacterium tuberculosis, son on yılda kanserden sonra en ölümcül hastalık olan tüberkülozun etkenidir. Çoklu ilaç ve ilaca dirençli suşların gelişimi, tüberküloz problemini daha da kritik kılmaktadır. Son 40 yılda, tedavi rejimine sadece bir molekül eklenmiştir. Genel olarak ilaç tasarım ve geliştirme programları, bakteri hücresi fonksiyonunda önemi olduğu bilinen proteinleri hedeflemektedir. M. tuberculosis, SecA2 ve ESX gibi özel protein ihracat sistemlerine sahiptir. Gereç ve Yöntemler: Bu çalışmada, protein atım sistemini hedefleyen antimikobakteriyel bir bileşiğin rasyonel geliştirilmesi integre cep modelleme ve sanal analiz kullanılarak gerçekleştirilmiştir. Objectives: Mycobacterium tuberculosis is the causative organism of tuberculosis, which is the most lethal disease after cancer in the current decade. The development of multidrug and broadly drug-resistant strains is making the problem of tuberculosis more and more critical. In the last 40 years, only one molecule has been added to the treatment regimen. Generally, drug design and development programs target proteins whose function is known to be essential to the bacterial cell. M. tuberculosis possesses specialized protein export systems like the SecA2 export pathway and ESX pathways. Materials and Methods: In the present communication, rational development of an antimycobacterial agent's targeting protein export system was carried out by integrating pocket modeling and virtual analysis. Results: The 23 identified potential lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like infrared and nuclear magnetic resonance spectroscopy, and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds showed profound antimycobacterial activity. Conclusion: We found that Q30, M9, M26, U8, and R26 molecules had significant desirable biological activity and specific interactions with Sec of mycobacteria. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidates with fewer side effects.

Emerging Extracellular Molecular Targets for Innovative Pharmacological Approaches to Resistant Mtb Infection

“…Additionally, it was recently shown that the SecA2 pathway activates the ATK kinase checkpoint protein, resulting in the formation of double-strand breaks (DBSs) in host DNA [ 64 ]. Several compounds have been identified as potential inhibitors of Sec pathways, including analogs of the dye rose Bengal, thiouracil analogs and thiazolidine derivatives [ 65 , 66 , 67 ].…”

“…Different thiazolidine derivatives (n.29, Table 5 ) were tested for anti-mycobacterial activity. Khare et al discovered Q30, M9, M26, U8, and R26 molecules as potent SecA2 inhibitors among 30 identified compounds [ 67 ]. These compounds have shown promising in vitro antimycobacterial activity and may open up a new path for the development of novel tuberculosis therapies.…”