Exploration of Isoxazole‐Carboxylic Acid Methyl Ester Based 2‐Substituted Quinoline Derivatives as Promising Antitubercular Agents

Abstract

In pursuit of potent anti‐TB agents active against drug resistant tuberculosis (DR‐TB), herein we report synthesis and bio‐evaluation of a new series of isoxazole‐carboxylic acid methyl ester based 2‐substituted quinoline derivatives. Preliminary evaluation indicated selectivity towards Mtb H37Rv, with no inhibition of non‐tubercular mycobacterial (NTM) & bacterial pathogen panel. Out of 36 synthesized compounds, majority exhibited substantial inhibition of Mtb H37Rv (MIC 0.5–8 μg/mL). Cell viability test against Vero cells revealed no significant cytotoxicity. Further, screening against drug resistant strains (DR‐Mtb) found hit compound displaying promising potency (MIC 1–4 μg/mL). Structure optimization of the hit led to the identification of lead compound demonstrating potent inhibition of both drug‐susceptible Mtb (MIC 0.12 μg/mL) and drug‐resistant Mtb (MIC 0.25–0.5 μg/mL) along with a high selectivity index (SI) >80. Taken together, with appreciable selectivity and potent activity, these chemotypes show prospect to be turned into a potential anti‐TB candidate.

Isoxazole carboxylic acid methyl ester-based urea and thiourea derivatives as promising antitubercular agents

“…Similarly, the deterioration of potency for 4tc indicated that introduction of methoxy group adjacent to ureido moiety probably caused reduced interaction of ureido motif with target. This could further be justified from the fact that a similar modification in our earlier work resulted in producing most potent molecule wherein, the methoxy group possibly hindered metabolic susceptibility of adjacent amide linkage [ 25 ]. On the other hand, 4te was found to be poorly active towards Mtb, indicating importance of ester moiety in imparting lipophilicity required for permeability through cell wall of Mtb, that is consistent with previous literature [ 17 ].…”

“…Several isoxazole carboxylic acid alkyl ester derivatives like II depicted in Fig. 1 are reported in literature as potent inhibitor of not only drug-susceptible (DS) but also drug-resistant (DR) Mtb [ 19 – 25 ]. Apart from isoxazole acid and ester, the peculiar and versatile anti-TB attributes of isoxazole moiety as an anti-TB pharmacophore could be well judged from several representative compounds reported in literature [ 26 – 28 ].…”

Bioevaluation of quinoline‐4‐carbonyl derivatives of piperazinyl‐benzothiazinones as promising antimycobacterial agents

“…Treatment of aforementioned intermediate 4a-e with excess of piperazine in ethanol led to the formation of corresponding 2piperazinyl benzothiazinones 5a-e as key intermediate. Meanwhile, by employing Pfitzinger reaction conditions, [54,55] 5-substituted isatins 6a-f were converted to 2-methylcinchonic acid derivatives 7a-f upon refluxing with acetone in presence of sodium hydroxide as a base in aqueous S C H E M E 1 Synthetic route to 4-quinolinocarbonyl piperazine-substituted benzothiazinones. Reagents and conditions: (i) concentrated HNO 3 , concentrated H 2 SO 4 , 0°C-heating, 2 h, 70%-84%; (ii) a. SOCl 2 , cat.…”

An Efficient Synthesis, Antimicrobial Evaluation and In Silico Studies of 1,2,3‐Triazolyl‐isoxazolyl‐ethanol Derivatives

“…[24][25][26][27] 1,2,3-Triazole-containing compounds received more attention due to their varied biological activities such as antifungal, [28][29][30][31][32][33][34] antimicrobial, [35,36] antivirals, [37,38] antimalarial, [39,40] anticancer [41][42][43] and anti-inflammatory activities. [44,45] The isoxazole containing natural and synthetic compounds reported for a wide range of biological activities such as antimicrobial, [46,47] antibacterial, [48][49][50] antifungal, [51,52] antitubercular, [16,[53][54][55] antiviral, [56,57] anticancer, [58][59][60] and anti-inflammatory. [61][62][63] Some of the FDA-approved and commercialized drugs containing isoxazole and triazole pharmacophore are shown in Figure 1 1) The hybrids of 1,2,4-triazole drugs by clubbing with azole or structural modifications of the fluconazole, isavuconazole, ravuconazole and albaconazole were reported for potential antifungal activity.…”

“…1,2,3‐Triazole‐containing compounds received more attention due to their varied biological activities such as antifungal, [28–34] antimicrobial, [35,36] antivirals, [37,38] antimalarial, [39,40] anticancer [41–43] and anti‐inflammatory activities [44,45] . The isoxazole containing natural and synthetic compounds reported for a wide range of biological activities such as antimicrobial, [46,47] antibacterial, [48–50] antifungal, [51,52] antitubercular, [16,53–55] antiviral, [56,57] anticancer, [58–60] and anti‐inflammatory [61–63] …”