Molecular modeling studies and anti-TB activity of trisubstituted indolizine analogues; molecular docking and dynamic inputs

Abstract

A series of trisubstituted indolizine analogues has been designed as a result of a fragment-based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 and 11.3 μg/mL, respectively. A molecular docking study was also conducted to evaluate the stability of the active compounds, and compound with ethyl substitution at second position of indolizine nucleus showed the highest free binding energy of ΔG -24.11 (kcal/mol), a low clash score of 3.04, and high lipo score of -13.33. Indolizine analog with ethyl substitution at second position demonstrated Molecular Mechanics/Generalized Born Surface Area (-23.85 kcal/mol). Two molecular dynamics studies were computed (100 ps and 50 ns) to calculate the relationship between the potential and kinetic energies of the active anti-TB compound with time and temperature. The discovery of this lead may have a positive impact on anti-TB drug discovery.

Anti-Tubercular Activity of Substituted 7-Methyl and 7-Formylindolizines and In Silico Study for Prospective Molecular Target Identification

“…Lastly, compound 4, containing a formyl functional group at the seventh position of the indolizine nucleus and a bromo group at the para position of the benzoyl moiety located at third position of indolizine ring, was found to exhibit the most promising anti-mycobacterial activity by displaying MIC at 4 µg/mL and 32 µg/mL against H37Rv and MDR strains of Mycobacterium tuberculosis, respectively. This finding strongly corroborates the reported preliminary structure-activity result of the 7-acetyl indolizine series [31], in which the presence of a polar group (carbonyl) at the seventh position of the indolizine ring was an important criteria for retaining anti-mycobacterial inhibition. Note: MIC (minimum inhibitory concentration).…”

“…Recently, our group started investigating multifunctionalized indolizine pharmacophores for their chemistry, structural elucidation, and pharmacological properties, including their anticancer properties [10], cyclooxygenase-2 (COX-2) inhibition properties [14,27], and larvicidal activity against Anopheles arabiensis [21]. In continuation of our effort to identify novel potent anti-TB agents of cyclic depsipeptides [28] and heterocyclic origin [29][30][31][32][33][34], we previously identified a series of 7-acetyl indolizines exhibiting interesting anti-mycobacterial activity. A preliminary structure-activity relationship was determined to demonstrate that the indolizine (1) displayed the most potent activity at 11 µg/mL against both H37Rv and MDR strains of MTB ( Figure 1) [31].…”

“…In continuation of our effort to identify novel potent anti-TB agents of cyclic depsipeptides [28] and heterocyclic origin [29][30][31][32][33][34], we previously identified a series of 7-acetyl indolizines exhibiting interesting anti-mycobacterial activity. A preliminary structure-activity relationship was determined to demonstrate that the indolizine (1) displayed the most potent activity at 11 µg/mL against both H37Rv and MDR strains of MTB ( Figure 1) [31]. In the present investigation, we explore the impacts of the functionalization at positions 2 and 7 of a novel series of 3-substituted benzoylindolizine (2) on the anti-tubercular activity against H37Rv and MDR strains of MTB.…”

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

“…[34][35][36] Herein, we report the anti-TB activity of THP derivatives against H37Rv and multidrug-resistant (MDR) strains of MTB. On the basis of our previous findings on the promising anti-TB activity of THP scaffolds 27,28 on whole-cell anti-TB properties and in a continuous effort to identify novel heterocyclic scaffolds that demonstrate potential anti-TB activity, [37][38][39][40] we screened six 1,2,3,4-tetrahydropyrimidinone (1a-d) and 1,2,3,4-tetrahydropyrimidinethione (2a-b) analogues (Scheme 1) for whole-cell anti-TB activity against H37Rv and MDR strains of MTB by the resazurin microplate assay (REMA) plate method.…”

Anti-tubercular Potency and Computationallyassessed Drug-likeness and Toxicology of Diversely Substituted Indolizines

“…These drugs include, GSK 2556286 (D3); 13 TBAJ-587 (D4) from diarylquinoline; 13 TBI-223 (D5) from oxazolidinone; 14 spectinamide 1810 (D6) and spectinomycin analogues, 15 BTZ-043 (D7), 16 GSK 070 and GSK 3036656 (D8) from oxaborole; 13 contezolid (MRX-4/MRX-1) (D9) from oxazolidinone; 17 OPC-167832 (D10), a 3,4-dihyrdocarbostyril derivative; 18 Macozinone (PBTZ169) (D11), a piperazinobenzothiazinone derivative; [19][20] clofazimine (TBI-166) (D12) from riminophenazine; 21 TBA-7371 (D13) from azaindole; 13 and Sutezolid (D14) from oxazolidinone. [22][23][24][25] In continuation of our effort to investigate novel heterocyclic agents for multi-drug resistant anti-tubercular property [26][27][28][29] and in addition to the aforementioned chemical structures, the heterocyclic scaffold of indolizine ( Figure 2) has shown promising anti-tubercular activity in early experiments. 28,30 While the analgesic, 31 anticancer, [32][33] antidiabetic, 34 antihistaminic, 35 antiinflammatory, [36][37] antileishmanial, 38 antimicrobial, 39 antimutagenic, 40 antioxidant, 41 antiviral, 42 larvicidal [43][44] and herbicidal 45 activities of this pharmacophore is relatively well-established, data on its anti-tubercular activity are still in accrual.…”