Synthesis of novel quinoline‐thiosemicarbazide hybrids and evaluation of their biological activities, molecular docking, molecular dynamics, pharmacophore model studies, and ADME‐Tox properties

Abstract

In the present study, a novel series of N‐((substituted)carbamothioyl)‐2,4‐dimethylquinoline‐3‐carboxamide (7a‐7s) was synthesized by microwave‐assisted method. Structure of these derivatives was examined by spectroscopic techniques such as 1H NMR, 13C NMR, FT‐IR, and ESI‐MS. Further, the novel synthesized compounds were evaluated for their in‐vitro biological activities against antibacterial, antifungal, antimalarial, and antituberculosis activity as well as for in‐silico study. The antimalarial results demonstrated that compounds 7c and 7q (0.02 μg/mL) have notable potency against Plasmodium falciparum compared with chloroquine (0.02 μg/mL); compounds 7l (0.10 μg/mL), 7e, 7s (0.19 μg/mL), 7b, 7p (0.15 μg/mL), 7a, 7f, and 7f (0.25 μg/mL) also exhibited good activity against P. falciparum compared with quinine (0.26 μg/mL) as standard drug. Docking was performed on PFDHFR‐TS, given the effect of compounds against the P. falciparum strain was excellent in comparison with standard drug. Molecular docking suggested that compounds 7b, 7i and 7c, 7e, and 7l closely bind with the active site of protein 3JSU and 4DP3, respectively, and compared with biological activity. We have also carried out molecular dynamics simulation on the best dock compound 7e complex with PDB: 3JSU to check the stability of docked complex and their molecular interaction. The calculated ADME‐Tox descriptors for the synthesized compounds validated good pharmacokinetics properties, suggesting that these compounds could be used as hit for the development of the new active agents.

Computational Approaches in Preclinical Studies on Drug Discovery and Development

“…Therefore, the availability of ligand data is essential to the construction of pharmacophore models. In recent years, there have been many cases of using pharmacophore models to screen promising compounds with outstanding ADMET properties (Nandekar et al, 2016 ; El-Zahabi et al, 2019 ; Mohan et al, 2020 ; Patel D. B. et al, 2020 ; Rawat and Verma, 2020 ). For example, Nandekar et al ( 2016 ) generated and validated a pharmacophore model to screen anticancer compounds acting via cytochrome P450 1A1 (CYP1A1).…”

Medicinal chemistry updates on quinoline- and endoperoxide-based hybrids with potent antimalarial activity

“…Hybrid 51 also acted by inhibiting cell invasion by the parasites, as revealed by the infection rate measured 4 hours after the addition of parasites to the cells. The chemical structures of these hybrids (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59) are given in Fig. 9 and their IC 50 values are shown in Table 7.…”

An Expeditious Approach to the Synthesis of Novel Quinolino and Diazacino Condensed Analogues of Azepino [3, 2-b] Carbazole-2-one of Medicinal Interest

“…15 It has been reported that quinoline molecular framework embellished with styryl motif show HIV integrase inhibitor activity. 16 It is evident from the literature that heterocyclics that contain quinolones, 17 carbazoles, 18 azepinones 19 etc. in their molecules exhibit a wide variety of biological activities such as, anti-mycobacterial, 20 anti-leishmanicidal, 21 antitumor, 22 anti-proliferative 23 and anti-leukemic 24 etc.…”