**1. Introduction**

Tuberculosis (TB) as both an acute and chronic infectious disease is still unbeaten and represents an important social, medical, and biological challenge for the healthcare worldwide [1]. The infection caused by *Mycobacterium tuberculosis* strains is most often located in the respiratory tract from which it is transmitted in the population by aerosols. At the same time, mycobacteria can be disseminated also to other organs. However, it is now well acknowledged that even in its primary location, the TB pathogen is present in different microenvironments and thus in various metabolic states, which substantially complicates the treatment [2]. According to the last Global Tuberculosis Report issued by the World Health Organization (WHO) [3], in 2018 the death rate was estimated to be about 1.45 million people. Among the estimated 10 million new cases of TB, 3.4% had multidrug-resistant TB or rifampicin-resistant TB (MDR/RR-TB). This number increased to 18% in previously treated cases, with the highest proportions (>50% in previously treated cases) in countries of the former Soviet Union. Although efficient TB treatment is available, only 7 million new cases were treated for the disease in 2018, while an estimated 3 million patients did not have access to quality care or were not reported, and only one in three people with drug-resistant TB accessed care [3].

In addition to interventions in the social area and point-of-care management of TB, one of the key challenges in making the fight against TB more effective is to improve treatment options. The current chemotherapy for the drug-sensitive TB takes about six months and requires administration of four different medicines (isoniazid, rifampicin, ethambutol, pyrazinamide) to avoid development of drug resistance. The length of the treatment and its adverse effects result in bad compliance and thus it is imperative to find novel drugs and regimens that would be less demanding on patients [4].

During recent years, three novel drugs against TB were approved. These are bedaquiline [5], delamanid [6] and pretomanid [7], which are currently undergoing several clinical trials aimed at treatment of the drug-resistant TB, as well as at shortening standard TB treatment [8]. The efforts and hope for better TB drugs are exemplified also by the pipeline of several new molecules, that are currently at different stages of clinical development. Among them there are inhibitors of protein

synthesis from the oxazolidinone family (delpazolid, sutezolid, contezolid, TBI-223), inhibitor of leucyl-tRNA synthetase (GSK3036656), inhibitor of DNA gyrase B (SPR720), compounds interfering with the respiratory chain of a TB pathogen (telacebec, TBI-166), a cell wall inhibitor targeting MmpL3 transporter (SQ109) and four compounds targeting another cell wall target, DprE1. These are BTZ043, TBA-7371, OPC-167832, and macozinone (Figure 1) [4,8]. In this review we will present the key findings towards the discovery and development of macozinone, an optimized benzothiazinone, which currently appears to be the most advanced DprE1 inhibitor.

**Figure 1.** DprE1 inhibitors in clinical development.
