Triazole-Containing Hybrids With Anti- Mycobacterium Tuberculosis Potential – Part I: 1,2,3-Triazole

Abstract

Tuberculosis regimens currently applied in clinical practice require months of multidrug therapy, which imposes a major challenge of patient compliance and drug resistance development. Moreover, because of the increasing emergence of hard-to-treat tuberculosis, this disease continues to be a significant threat to the human population. 1,2,3-triazole as a privileged structure has been widely used as an effective template for drug discovery, and 1,2,3-triazole-containing hybrids that can simultaneously act on dual or multiple targets in Mycobacterium tuberculosis have the potential to circumvent drug resistance, enhance efficacy, reduce side effects and improve pharmacokinetic as well as pharmacodynamic profiles. Thus, 1,2,3-triazole-containing hybrids are useful scaffolds for the development of antitubercular agents. This review aims to highlight recent advances of 1,2,3-triazole-containing hybrids with potential activity against various forms of M. tuberculosis, covering articles published between 2015 and 2020. The structure–activity relationship and the mechanism of action are also discussed to facilitate further rational design of more effective drug candidates.

Molecular Hybrids of Pyazolo[3,4-b]pyridine and Triazole: Design, Synthesis and In Vitro Antibacterial Studies

“…According to the literature, triazole and pyrazolo[3,4- b ]pyridine scaffolds have been the most extensively studied for their medicinal characteristics among nitrogen-containing heterocycles. To combat drug resistance, there has recently been a surge in interest in the meticulous use of 1,2,3-triazole in the creation of new antibacterial agents [ 13 , 14 , 15 , 16 , 17 ]. Some 1,2,3-triazole-containing hybrids, including cefatrizine, tazobactam, and radezolid, have already been used in clinics or are currently undergoing clinical trials for the treatment of infections brought on by a variety of bacteria, including MRSA [ 9 , 13 , 14 , 15 , 16 , 17 ].…”

“…To combat drug resistance, there has recently been a surge in interest in the meticulous use of 1,2,3-triazole in the creation of new antibacterial agents [ 13 , 14 , 15 , 16 , 17 ]. Some 1,2,3-triazole-containing hybrids, including cefatrizine, tazobactam, and radezolid, have already been used in clinics or are currently undergoing clinical trials for the treatment of infections brought on by a variety of bacteria, including MRSA [ 9 , 13 , 14 , 15 , 16 , 17 ]. To create new anti-MRSA candidates, the rational creation of hybrids incorporating 1,2,3-triazoles is an appealing method [ 18 , 19 ].…”

“…Enhanced paracellular and transcellular absorption characteristics of compounds with lower molecular weight and lipophilicity are anticipated [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], as well as a transporter influence on clearance, leading to improved renal excretion [ 28 , 29 ] and mild toxicity [ 30 ]. A molecule becomes a drug-like molecule (DLM) when it meets the requirements outlined by the “rule of 5” (Ro5).…”

Toxicity parameters of a new 1,2,4-triazole derivative when subcutaneously injected to guinea pigs

“…Interest in these compounds is shown not only by scientists engaged in organic synthesis, but also pharmacologists, biologists, specialists in veterinary medicine, pharmacy and agronomy (Bihdan et al, 2019;Palchykov et al, 2020). Such close attention from a wide range of the scientific community to 1,2,4-triazole derivatives needs a reasoned explanation; firstly, 1,2,4-triazole and its substitutes are very reactive (Tan et al, 2021), and secondly, their low toxicity and high pharmacological activity purposefully creates conditions for the prospective search for potential biologically active compounds (Xu et al, 2017).…”

“…However, despite this fact, resistant cases appeared a year after the introduction of these drugs in clinical practice, which reflects that the current efforts in the development of drugs are insufficient to completely eliminate the tuberculosis epidemic (Tan et al, 2021).…”