Design and Synthesis of Novel Indolizine Analogues as COX-2 Inhibitors: Computational Perspective and in vitro Screening

Chandrashekharappa, Sandeep; Venugopala, Katharigatta N.; Khedr, Mohammed A.; Padmashali, Basavaraj; Kulkarni, Rashmi S.; Venugopala, Rashmi; Odhav, Bharti

doi:10.5530/ijper.51.3.73

Cited by 35 publications

(17 citation statements)

References 47 publications

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“…Title compounds 5a , 5b , 5d , 5e , 5g , 5h , and 5i were prepared and the physicochemical constants were compared with a previous report [18] and tabulated in Table 1. The molecular structures of the test compounds are illustrated in Fig 3.…”

Section: Methodsmentioning

confidence: 99%

“…Indolizines are heteroaromatic compounds, and their synthetic analogues have reportedly demonstrated promising pharmacological properties [11]. Specifically, they have exhibited analgesic [12], anticancer [13, 14], antidiabetic [15], antihistaminic [16], anti-inflammatory [17, 18], antileishmanial [19], antimicrobial [20], antimutagenic [21], antioxidant [22], antitubercular [10, 23], antiviral [24], larvicidal [25], and herbicidal activities [26]. In continuation of our previous work aimed at developing such synthetic indolizine analogues as enoyl-[acyl-carrier] protein reductase enzyme inhibitors (Fig 2), we undertake the screening of substituted 7-methoxy-indolizine analogues (Fig 3) to determine their whole-cell anti-TB properties against H3Rv and MDR strains of MTB using the resazurin microplate assay (REMA) plate method.…”

Section: Introductionmentioning

confidence: 99%

“…Our group recently investigated various substituted indolizine scaffolds for their synthesis, crystallography, and pharmacological properties, including their anticancer properties [14], their larvicidal activity against Anopheles arabiensis [25, 27], and their cyclooxygenase-2 (COX-2) inhibition properties (Fig 4) [18, 28].…”

Section: Introductionmentioning

confidence: 99%

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Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues

et al. 2019

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Indolizines are heteroaromatic compounds, and their synthetic analogues have reportedly showed promising pharmacological properties. In this study, a series of synthetic 7-methoxy-indolizine derivatives were synthesised, characterised and evaluated for in vitro whole-cell anti-tuberculosis (TB) screening against susceptible (H37Rv) and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) using the resazurin microplate assay method. The cytotoxicity was evaluated using the MTT assay. In silico molecular-docking study was conducted for compounds 5a-j against enoyl-[acyl-carrier] protein reductase, a key enzyme of the type II fatty acid synthesis that has attracted much interest for the development of novel anti-TB compounds. Thereafter, molecular dynamic (MD) simulation was undertaken for the most active inhibitors. Compounds 5i and 5j with the methoxy functional group at the meta position of the benzoyl group, which was at the third position of the indolizine nucleus, demonstrated encouraging anti-TB activity against MDR strains of MTB at 16 μg/mL. In silico studies showed binding affinity within the range of 7.07–8.57 kcal/mol, with 5i showing the highest binding affinity. Hydrogen bonding, π-π- interactions, and electrostatic interactions were common with the active site. Most of these interactions occurred with the catalytic amino acids (Pro193, Tyr158, Phe149, and Lys165). MD simulation showed that 5j possessed the highest binding affinity toward the enzyme, according to the two calculation methods (MM/PBSA and MM/GBSA). The single-crystal X-ray studies of compounds 5c and 5d revealed that the molecular arrangements in these two structures were mostly guided by C-H···O hydrogen-bonded dimeric motifs and C-H···N hydrogen bonds, while various secondary interactions (such as π···π and C-H···F) also contributed to crystal formation. Compounds 5a , 5c , 5i , and 5j exhibited no toxicity up to 500 μg/mL. In conclusion, 5i and 5j are promising anti-TB compounds that have shown high affinity based on docking and MD simulation results.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues

et al. 2019

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“…In continuation of our effort to identify potential COX-2 inhibitors [14,15], in the present study, the anti-inflammatory activity of a series of phenylindolizine derivatives was evaluated by assessing the ability of the compounds to inhibit the COX-2 enzyme. In addition, molecular modeling studies were carried out to gain better insights into the structural requirements for achieving the high activity.…”

Section: Introductionmentioning

confidence: 99%

Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies

et al. 2019

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The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 μM, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents.

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“…In continuation of the synthesis and characterization of substituted indolizine analogs [35] for anti-tubercular [36], cyclooxygenase enzyme inhibition (COX-2) [37, 38], larvicidal [39, 40], and anticancer [41] activities, in the present investigation, we undertake the synthesis and perform a single crystal X-ray study on ethyl 3-benzoyl-2,7-dimethyl indolizine-1-carboxylate ( INLZ ) as a NANAS inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and structural elucidation of novel NmeNANAS inhibitors for the treatment of meningococcal infection

et al. 2019

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Neisseria meningitidis is the primary cause of bacterial meningitis in many parts of the world, with considerable mortality rates among neonates and adults. In Saudi Arabia, serious outbreaks of N. meningitidis affecting several hundreds of pilgrims attending Hajj in Makkah were recorded in the 2000–2001 season. Evidence shows increased rates of bacterial resistance to penicillin and other antimicrobial agents that are used in the treatment of the meningococcal disease. The host’s immune system becomes unable to recognize the polysialic acid capsule of the resistant N. meningitidis that mimics the mammalian cell surface. The biosynthetic pathways of sialic acid (i.e., N-acetylneuraminic acid [NANA]) in bacteria, however, are somewhat different from those in mammals. The largest obstacle facing previously identified inhibitors of NANA synthase (NANAS) in N. meningitidis is that these inhibitors feature undesired chemical and pharmacological characteristics. To better comprehend the binding mechanism underlying these inhibitors at the catalytic site of NANAS, we performed molecular modeling studies to uncover essential structural aspects for the ultimate recognition at the catalytic site required for optimal inhibitory activity. Applying two virtual screening candidate molecules and one designed molecule showed promising structural scaffolds. Here, we report ethyl 3-benzoyl-2,7-dimethyl indolizine-1-carboxylate (INLZ) as a novel molecule with high energetic fitness scores at the catalytic site of the NmeNANAS enzyme. INLZ represents a promising scaffold for NmeNANAS enzyme inhibitors, with new prospects for further structural development and activity optimization.

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Design and Synthesis of Novel Indolizine Analogues as COX-2 Inhibitors: Computational Perspective and in vitro Screening

Cited by 35 publications

References 47 publications

Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues

Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues

Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies

Design, synthesis, and structural elucidation of novel NmeNANAS inhibitors for the treatment of meningococcal infection

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