Research | Haridasbrode

Research Summary

1. Development of inhibitors targeting drug-resistant tuberculosis

Tuberculosis (TB) is a major cause of deaths, especially in Asia and African subcontinent. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have complicated the TB treatment. The emergence of COVID-19 has further complicated scenario wherein the co-existence of tuberculosis and COVID-19 has thrown a challenge in treating such cases. The two important antituberculosis drugs, i.e. Bedaquiline and Delamanid, have novel mode of action and are available option for current treatment of drug-resistant tuberculosis (figure 1A, [1]). It should be noted that Bedaquiline is not advised for people with arrhythmias as it may prolong QT interval. The QT prolongation has also been observed in case of Delamanid. Hence, there is a need for safer and more effective therapy for treating TB. In this project, we are developing a preclinical candidate effective against drug-resistant tuberculosis which will be devoid of cardiotoxicity. The focused medicinal chemistry based approach is being used to generate the inhibitors. The screening of compounds is done in collaboration with biologists.

We identified primary hits from screening of 10,000 compounds using M. smegmatis followed by screening of the positives on M. tuberculosis H37Rv. The analysis using Lipinski's rule of five for druglikeness and excluding compounds having reactive groups revealed 10 chemically tractable scaffolds with promising antituberculosis activity [2]. One of the hit (H11) from the screen was modified to generate more potent antituberculosis compound 1 (figure 1B). Compound 1 inhibited MDR and Pre-XDR isolates of Mycobacterium at 2 µg/mL and 8 µg/mL, respectively [3]. The detail structure-activity-relationship (SAR) resulted in identification of pharmacophore. Further modifications are in progress to generate a preclinical candidate from this series.

Figure 1: (A) Mode of action of antituberculosis drug; (B) Development of inhibitors

In another example, we developed thiazole-based antituberculosis agent which is devoid of pyridine substituent (Compound 2, figure 1B). These compounds showed activity against dormant M. tuberculosis H37Ra and limited activity against drug resistant TB isolates. The docking of 2 in the active site of Mtb CTP (cytidine triphosphate) synthase PyrG revealed that the thiazole-nitrogen of 2 interacts with magnesium ion whereas ester functionality is involved in hydrogen bond interactions with protonated Lys24 and Lys46 residues of PyrG [4].

Further, novel 1,3,4-oxadiazoles with limited activity against drug-resistant tuberculosis have been developed [5]. The 3-aryl substituted imidazo[1,2-a]pyridines were synthesized and evaluated against M. tuberculosis H37Rv. Compound 3 (figure 1B) showed MIC 2.3 μg/ml against M. tuberculosis H37Rv. The docking of 3 in the active site of Mycobacterium tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 3 with Tyr389 and Trp312 residues of Mtb QcrB (figure 2). Further, a modified process for the synthesis of 4 (Q203) was developed.

Figure 2: Docking of Q203 and compound 3 in the active site of Mtb QcrB (PDB ID for Mtb QcrB: 1SJ2)

2. Development of antibacterials against ESKAPE pathogen:

Antimicrobial resistance (AMR) is a growing issue claiming millions of lives all over the world. A dearth of novel antibiotics active against rapidly emerging drug-resistant pathogens has made it critical to search for potential new efficacious antibiotics. In this context, we used drug repurposing approach to develop a Nitazoxanide and Linezolid combination which showed effectiveness both in vitro and in vivo against Linezolid susceptible and -resistant S.aureus [7]. In another example, Pyrvinium pamoate potentiated Levofloxacin against Levofloxacin resistant Staphylococcus aureus [8]. Further, inhibitors effective against Gram-negative bacteria have been identified and are undergoing hit to lead progression.

3. Development of synthetic methodologies:

Building a chemically diverse compound library is an important starting point in any drug discovery. Under this project, synthesis of methylene-tethered arylsulfonation and benzotriazolation of imidazopyridines (figure 3A) has been achieved [9]. The activation of DMSO by Selectfluor was a key for this transformation. Further, β-acyl allyl sulfones/ β-acyl allyl benzotriazoles with excellent atom economy from readily available acetophenones/arylacetylenes, aryl sulfinates/benzotriazoles, and DMSO was achieved [10]. Important to note that DMSO acted as dual carbon synthon affording a transition metal-free construction of two C-C & one C-S or two C-C & one C-N bonds in one pot (figure 3B). In another example, Selectfluor mediated regioselective π-extended [3+1+1] annulation using imidazopyridines, acetophenones and DMF as carbon synthon has been described [11]. Importantly, DMF has acted as one carbon synthon in [3+1+1] annulation reaction whereas two carbon synthon in the formation of five-membered bridged chroman-4-one derivatives (figure 3C). Further, we demonstrated the development of biologically diverse scaffolds from nitroarene/ nitro(hetero)arenes using a key synthetic strategy [12]. Mapping of the synthesized scaffolds revealed their contribution to underrepresented chemical space (figure 3D).

Figure 3: (A) Methylene-tethered arylsulfonation and benzotriazolation of imidazopyridines; (B) β-acyl allyl sulfones/ β-acyl allyl benzotriazoles from acetophenones and aryl sulfinates/benzotriazoles; (C) Regioselective [3+1+1] annulation of imidazopyridines and acetophenones in DMF; (D) Iron mediated reductive cyclization/oxidation of nitroarene/ nitro(hetero)arenes for the generation of chemically diverse scaffolds.

References:

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