Studies on Isoniazid Derivatives through a Medicinal Chemistry Approach for the Identification of New Inhibitors of Urease and Inflammatory Markers

Abstract

A library of thiosemicarbazide derivatives of isoniazid 3–27 , was synthesized and evaluated for their anti-inflammatory and urease inhibition activities, by using in vitro bioassays. Among these compounds 9 , 10 , 12 , 21 , and 26 were identified as new derivatives. Prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) and infections caused by Helicobacter pylori (ureolytic bacteria), are the two most significant causes of gastric and peptic ulcers. We focused on the identification of the dual inhibitors of inflammation and urease enzyme. Compound 23 was identified as the best dual inhibitor of inflammation (ROS; IC 50 = 12.3 µg/mL), and urease enzyme inhibition activity (IC 50 = 22.4 µM). Many of these compounds showed comparable activities to the standard anti-inflammatory drug (ibuprofen, IC 50 = 11.2 µg/mL) and urease inhibitor (thiourea/acetohydraoxamic acid, IC 50 = 21.1/20.3 µM). Compound 12 was found to be the most potent urease inhibitor (IC 50 = 12.3 µM) and good inhibitor of inflammation (IC 50 = 27.7 µg/mL). Compounds 19 , 11 , 13 , 9 , 17 , 10 , and 16 , were also found to be potent inhibitors of urease. Cytotoxicity was also evaluated and all the compounds were found to be non-cytotoxic, except compound 18 and the parent drug isoniazid (IC 50 = 29.5 and 28.5 µM, respectively).

Phenylisoxazole-3/5-Carbaldehyde Isonicotinylhydrazone Derivatives: Synthesis, Characterization, and Antitubercular Activity

“…For compounds 3, 4, 6, and 8, the chemical shifts of the C-4´ć arbon appeared in the range of 140.47-140.0 ppm. ese results are in agreement with the resonance lines of the pyridine carbons found for other derivatives from isoniazid and isoniazid hydrazones [48,49]. For compounds 1-4 and 6-8, the resonance lines observed at 139.11-135.62 ppm were assigned to the azomethine carbons.…”

N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation

“…Therefore, urease is considered as a virulence factor playing an essential role for establishment of H. pylori colonisation in human. Therefore, urease inhibitors could serve as drugs for treating H. pylori caused disease such as gastritis and peptic ulcers 6 .…”

Urease Inhibition and Structure‐Activity Relationship Study of Thiazolidinone‐, Triazole‐, and Benzothiazole‐Based Heterocyclic Derivatives: A Focus Review

“…The inhibitors of the urease can be categorized into two classes; substrate like inhibitors (hydroxyurea, hydroxamic acids) and mechanism based inhibitors (phosphorodiamidates). During the past years, extensive research has been done on the design and development of urease inhibitors such as hydroxamic acids, [51] urea and thiourea derivatives, [52] polyphenols, [53] isoniazids, [54] catechol-based inhibitors, [55] flavonoids, [56] coumarins, [57] indoles, [58] chalcones, [59] thiazoles, [60] thiazolidinones, [61] benzothiazoles, [62] benzoxazoles, [63] benzimidazoles, [64] barbituric acid and thiobarbituric acid derivatives, [65] quinazolinones, [66] triazoles, [67] phosphoramides, [68] sulfonamides, [69] thiadiazoles, [70] oxadiazoles, [71] thiosemicarbazones, [72] diamides, [73] benzenesulfonohydrazides [74] and many more. The most effec-tive inhibitors of urease cited in the literature are phosphorodiamide and phosphorotriamide derivatives such as NBPT (N-n butylthiophosphorictriamide), PPD (phenylphosphorodiamidate), NBPTO (N-n butylphosphorictriamide and flurofamide (Ndiaminophosphoryl-4-fluorobenzamide) [75] (Figure 6).…”