In silico Physicochemical Bioactivities and Toxicities Prediction of 3-chloro-6-arylpyridazines and 6-aryl- 4,5-dihydropyridazine-3(2H)-thiones having Antitubercular Activity

Abstract

Purpose: In the present study, antitubercular activities and in silico physicochemical toxicities and bioactivity profile of some 3-chloro-6-arylpyridazines (3a-d) and 6-aryl-4,5-dihydropyridazine-3(2H)-thiones (4a-d) are studied. Approach: The compounds (3a-d) and (4a-d) were evaluated as antitubercular agents against Mycobacterium tuberculosis H37Rv by screening through in vitro Microplate Alamar Blue Assay (MABA) method. Findings: In silico physicochemical parameter revealed that the entire compounds follow Lipinski's rule-of-5 to become a "drug like" molecule. ADME (absorption, distribution, metabolism and excretions) profile prediction has shown that all the compounds can be absorbed through human intestine (HIA +), Caco-2 cell (Caco-2 +) and can cross blood brain barrier (BBB +), they all are non-substrate and non-inhibitor of p-glycoprotein. Compounds 4a-d are inhibitor of human microsomal enzyme like CYP 450 1A2, CYP 450 2C19 and CYP 450 3A4. Research limitations/implications: Compounds 4a-4d are better ligand for enzyme inhibition than 3a-d compounds. The MIC of compounds 4a-d and 3a is 6.25 µg/ml. They are potent than compound 3b-d with MIC 12.5 µg/ml. Originality: Toxicity prediction indicated that compounds 3a-3d and 4a-d are non-carcinogenic and non-mutagenic. Bioactivity prediction for compounds 3a-3d and 4a-d indicated better ligand as enzyme inhibitor in comparison to standard.

Synthesis of 1,2,4‐triazolopyridazines, isoxazolofuropyridazines, and tetrazolopyridazines as antimicrobial agents

“…[1,2] The pyridazinones are especially a significant class of compounds due mainly to their many biological activities. [3] Also, the pyridazinone and pyridazine derivatives have possessed different types of biological and pharmacological activities such as antimicrobial, [4] antihypertensive, [5] anti-tubercular, [6] anti-secretory, anti-ulcer, antihistamine, [7] analgesic activity, [8] antifeedant, herbicidal, and molluscicidal activities, [9] treat of cardiovascular, [10] anticonvulsant, [11,12] and antiepileptic. [13] Azolopyridazine derivatives showed pharmaceutical and biological activity such as anxiolytic activity without the side effects.…”

Synthesis and antimicrobial activity of new 1,2,4‐triazole, 1,3,4‐oxadiazole, 1,3,4‐thiadiazole, thiopyrane, thiazolidinone, and azepine derivatives

“…Moreover, the pyridazine derivatives have diverse types of biological activity such as anti-inflammatory and analgesic activity, [40] antimicrobial, [41] antitubercular, [42] and antisecretory, anti-ulcer, and antihistamine. [43] Also, more scientific researchers have been published in the field of medicinal chemistry containing heterocyclic compounds that possess multiple biological and pharmaceutical activities.…”

Benzimidazole Molecule Hybrid With Oxadiazole Ring as Antiproliferative Agents: In-Silico Analysis, Synthesis and Biological Evaluation

“…The absorption percentage (% Ab) was also calculated by using the following formula: %Ab = 109 -[0.345 x TPSA] (Table 3). These properties are calculated on the basis of Lipinski's rule of five, which states that any compound considered as drug should have partition coefficient less than 5, its polar surface area within 140Ų, it should have H bond acceptor less than 10, it should have H bond donor less than 5 and its molecular weight within 500 dalton [41][42][43][44][45][46].…”

“…The compounds were also checked for bioactivity by calculating activity score for different target such as GPCR (G-protein coupled receptor) ligand, ion channel modulator, kinase inhibitor, nuclear receptor ligand [29,[45][46]. The compounds were showed good GPCR ligand affinity and compound 4c, 4f and 4k showed excellent GPCR ligand affinity.…”

“…Compound 4v is also shown better ligand for enzyme inhibition and GPCR ligand as per in-silico data prediction (Enzyme inhibitor >GPCR ligand >Kinase inhibitor >Protease inhibitor >Ion channel modulator> Nuclear receptor ligand). A molecule having bioactivity score more than 0.00 is most likely to exhibit considerable biological activities, while values -0.50 to 0.00 are expected to be moderately active and if score is less than -0.50 it is presumed to be inactive [45][46][47][48]. The most promising compounds as per the bioactivity scores were identified such as 3iii, 4iii and 4v which are predicted to act by more than three mechanisms (Table 5).…”