## 1 Introduction  
Tuberculosis (TB) is still a leading cause of death from an infectious agent. According to the World Health Organization's 2020 Global Tuberculosis Report, over 10 million people became ill with the disease in 2019 [1]. Action must be taken to combat this continuing public health threat. TB is caused by the bacterium _Mycobacterium tuberculosis_ (Mtb) and spread by aerosols of an infected person through a cough or sneeze. Treatment of individuals infected with TB consists of several medications that are taken together for 6-9 months. First-line drugs include isoniazid (INH), rifamp (RIF), ethambuttol (EMB) and pyrazinamide (PZA) [1]. Other barriers, such as lengthy treatment regimens and access to care, have made adherence to treatment challenging. Shorter treatment schedules are strongly desired. Despite the advances in drug therapies and modern medications, such as bedaquiline, delamamid and pretomamid, there is a need for comprehensive drug combinations and new treatment regimens to combat drug resistant TB [2]. Consideration of how Mtb survives onslaughts of chemotherapies gives insight into more effective treatment. Investigating the mechanism of action of antibiotics provides critical information that can be used to ultimately cure TB infections [3]. Targets within energy metabolism processes, specifically those involved in the oxidative phosphorylation pathway, have become of increased interest. Mtb can persist in a hypoxic, non-replicating, drug-tolerantstate [4]. It has been demonstrated that interrupting oxidative phosphorylation in Mtb is an encouraging strategy [5; 6; 7]. While compounds have been made to inhibit various targets within the oxidative phosphorylation pathway, limitations have been observed, including the inability to inhibit oxygen respiration and clear Mtb infection due to a redundancy between the terminal oxidases cytochrome _bcc:aa\({}_{3}\)_ (cyt-_bcc:aa\({}_{3}\)_) and cytochrome _bd_ (cyt-_bd_) [8]. Cytochrome _bcc:aa\({}_{3}\)_ is the main aerobic terminal oxidase in Mtb [9]. The compound Q203 (**4**, Telacebec(r)) inhibits cytochrome _bcc_ by binding to the QcrB subunit, thereby inhibiting the function of the cytochrome _bcc:aa\({}_{3}\)_ super-complex [10]. When cytochrome _bcc:aa\({}_{3}\)_ is inactive, cyt-_bd_ is upregulated [11]. This adaptation provides protection against cytochrome _bcc:aa\({}_{3}\)_ inhibitors such as Q203. We have shown that targeting cyt-_bd_ in combination with Q203 is bactericidal against replicating and non-replicating Mtb [12]. This makes cyt-_bd_ an enticing target for the development of antituberculosis agents to effectively eliminate infection. Interested in the inhibition of this target, we screened a small set (56) of antibacterial compounds that originated from our decades-old antibacterial program. This led to the identification of cyt-_bd_ compounds like the thieno[3,2-_d_]pyrimidin-4-amines in which (**1**) is an example, the in vivo active optimized inhibitor ND-11992 (**2**) and hit compound **3** (Figure 1) [13]. The \(N\)-phenethylquinazolin-4-amine class, exemplified by compound **3** (Figure 1), has an IC\({}_{50}\) of 11 uM against _Mycobacterium bovis_ BCG and an IC\({}_{50}\) of 27 uM against _Mycobacterium tuberculosis_ H37 Rv as determined by our published ATP depletion assay [13]. This assay is purposefully run in the presence and absence of Q203 (**4**, a selective cyt-_bcc:aa\({}_{3}\)_ inhibitor) to indicate whether a compound inhibits alone or synergizes due to the conditional essentiality of cyt-_bd_ to maintain ATP homeostasis once cyt-_bcc:aa\({}_{3}\)_ is selectively inhibited by Q203. Compound **3** was inactive (IC\({}_{50}\) > 25 uM) in the absence of Q203 which is an indication of on-target potency based upon assay design. Similarly, compound **3** was amenable to chemical modifications and structure-activity relationship (SAR) development.