Abstract
NSAIDs and coxibs are associated with serious gastroinstestinal and cardiovascular side effects on their long term usage. Five hydrazones having chloro, methoxy, and nitro group substitutions were designed following a patent and extensive literature review. The designed compounds were evaluated in-silico for their pharmacokinetic and toxicity profile. Synthesis of the hydrazones was achieved through mechanochemistry (solvent-free) and conventional methods. Structures of the synthesized hydrazones were determined using spectroscopic methods namely; FTIR and NMR analyses. The synthesized hydrazones were evaluated for their anti-inflammatory activity in-vivo using Carageenan induced-edema in mice. Molecular docking study was conducted using crystal structures of COX-2, 5-LOX, and H +/K + ATPase.
All the designed compounds demonstrated plausible pharmacokinetics and apparent safety profile. These compounds exhibited statistically significant (p ≤ 0.005) anti-inflammatory activities at all doses in carrageenan-induced paw edema in the mice model. Careful analysis of their anti-inflammatory activity indicated possibly time-dependent edema inhibition at each dose. Moreso, compound TMB345 exhibited superior activity at 10mg/kg to reference drugs used, and also dose-dependent anti-inflammatory activity. However, all the synthesized hydrazones indicated a slow onset of action (4.58% - 23.66%) compared to those of reference drugs 35.50% and 33.21% for piroxicam and celecoxib respectively, this onset of action was improved as the dose increased. All the synthesized compounds notwithstanding indicated superior and longer duration of action (52.05% - 87.30%) compared to celecoxib (49.18%) and piroxicam (60.25%) used as reference drugs. Interestingly, all the p- nitrophenylhydrazones exhibited potent inhibition of biological targets used for the docking simulation. Although, celecoxib as a selective COX-2 inhibitor demonstrated marked lower binding energy compared to any of the compounds. This suggests that it is more selective for COX-2 compared to the designed compounds. Compound TMB345 had infinitesimally higher binding energy compared to omeprazole. Compound TMB345 had superior interactions in-silico with COX-2, 5-LOX, and H+/K+ ATPase compared to their approved marketed inhibitors celecoxib, zileuton, and omeprazole respectively. Also, compounds TMB345 formed two hydrogen bond interactions with key amino acids; SER-516 which is one of the two most important interactions for COX-2 related anti-inflammatory activity.
Also, the designed compounds exhibited high inhibitory potency against the proton pump (PP) demonstrating good interactions with key amino acids; CYS-813 and CYS-822 responsible for proton pump (PP) inhibitory activity. Therefore, compound TMB345 has been identified as a lead compound.
Babalola, S. (2023). NEW MULTI-TARGET DIRECTED p-NITROPHENYL HYDRAZONES; CONCEPTION, DESIGN, SYNTHESIS, IN-VIVO ANTI-INFLAMMATORY EVALUATION, AND IN-SILICO STUDIES AGAINST COX-2, 5-LOX, AND H+/K+ ATPASE. Afribary. Retrieved from https://track.afribary.com/works/my-thesis-2
Babalola, Sodeeq "NEW MULTI-TARGET DIRECTED p-NITROPHENYL HYDRAZONES; CONCEPTION, DESIGN, SYNTHESIS, IN-VIVO ANTI-INFLAMMATORY EVALUATION, AND IN-SILICO STUDIES AGAINST COX-2, 5-LOX, AND H+/K+ ATPASE" Afribary. Afribary, 20 Mar. 2023, https://track.afribary.com/works/my-thesis-2. Accessed 14 Nov. 2024.
Babalola, Sodeeq . "NEW MULTI-TARGET DIRECTED p-NITROPHENYL HYDRAZONES; CONCEPTION, DESIGN, SYNTHESIS, IN-VIVO ANTI-INFLAMMATORY EVALUATION, AND IN-SILICO STUDIES AGAINST COX-2, 5-LOX, AND H+/K+ ATPASE". Afribary, Afribary, 20 Mar. 2023. Web. 14 Nov. 2024. < https://track.afribary.com/works/my-thesis-2 >.
Babalola, Sodeeq . "NEW MULTI-TARGET DIRECTED p-NITROPHENYL HYDRAZONES; CONCEPTION, DESIGN, SYNTHESIS, IN-VIVO ANTI-INFLAMMATORY EVALUATION, AND IN-SILICO STUDIES AGAINST COX-2, 5-LOX, AND H+/K+ ATPASE" Afribary (2023). Accessed November 14, 2024. https://track.afribary.com/works/my-thesis-2