Insights into conformational and packing features in a series of aryl substituted ethyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates

Nayak, Susanta K.; Venugopala, Katharigatta N.; Chopra, Deepak; Row, Tayur N. Guru

doi:10.1039/c0ce00045k

Cited by 27 publications

(16 citation statements)

References 29 publications

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“…The test compounds 1,2,3,4-tetrahydropyrimidinone (1ac) and 1,2,3,4-tetrahydropyrimidinethione (2b) (Scheme 1) were synthesized using our previously reported procedures, 41 and novel compounds 1d and 2a were synthesized by following a similar procedure.…”

Section: Materials and Methods Chemistrymentioning

confidence: 99%

In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against Mycobacterium tuberculosis

Venugopala¹,

Tratrat²,

Pillay³

et al. 2020

DDDT

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Background and Purpose: Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors. Methods: The title compounds (1a-d) and (2a-b) were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry's Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed. Results: Of the compounds tested for anti-TB activity, pyrimidinone 1a and pyrimidinethione 2a displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound 2a was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds 1a and 2a. Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds. Conclusion: Pyrimidinone 1a and pyrimidinethione 2a were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.

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Section: Materials and Methods Chemistrymentioning

confidence: 99%

In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against Mycobacterium tuberculosis

Venugopala¹,

Tratrat²,

Pillay³

et al. 2020

DDDT

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“…The synthesis of 3,6-dihydropyrimidine analogs DHPM1-DHPM8 was achieved as illustrated in (Scheme 1). Starting from the first intermediate methyl 4-(4chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 1 which has been synthesized by Biginelli reaction by employing Lewis acid according to the procedure described in our previous paper [28]. The purification of the product was accomplished using ETOH by recrystallization method and the yield of the product was 66%.…”

Section: Chemistrymentioning

confidence: 99%

Antimosquito Properties of 2-Substituted Phenyl/benzylamino-6-(4- chlorophenyl)-5-methoxycarbonyl-4-methyl-3,6-dihydropyrimidin-1-ium Chlorides Against Anopheles arabiensis

Venugopala¹,

Gleiser²,

Chalannavar³

et al. 2014

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Eight novel dihydropyrimidine analogs named DHPM1-DHPM8 was synthesized in their hydrochloride salt form using one pot synthesis between methyl 2-chloro-4-(4-chlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate and substituted arylamines in isopropanol. The antimosquito effect of the test compounds were assessed against the adult mosquito Anopheles arabiensis. For adulticidal properties the test compounds were sprayed onto ceramic tiles and screened using the cone bio-assay method. The larvicidal activity was tested by monitoring larval mortality daily and up to 3 days of exposure. Repellency properties were tested in a feeding-probe assay using unfed female Anopheles arabiensis. Compounds DHPM1, DHPM4, DHPM5 and DHPM6 exerted larval mortality equivalent to temephos (trade name Abate, a commercial larvicidal compound). Compounds DHPM1 to DHPM5 repelled or knocked down 92 to 98% of mosquitoes exposed to rodent skin treated with the compounds. None of the compounds showed any significant activity against the adult mosquito Anopheles arabiensis.

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“…Chopra and coworkers studied the crystal structures of a series of compounds related to structure 18, that is, with X = F, Cl, Me, OMe, NMe 2 , and Y = O [74] and S [75]. These Guru Row and coworkersstudied the crystal structures of a series of fluorinated compounds; Figure 1.13 shows that CH/π , CH/F and CH/O hydrogen bonds cooperatively work in stabilising the crystal conformation and network [76].…”

Section: Crystal Packingmentioning

confidence: 99%

The CH/π Hydrogen Bond: Implication in Crystal Engineering

Nishio¹,

Umezawa

Suezawa

et al. 2012

The Importance of Pi‐Interactions in Crystal Engineering

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Insights into conformational and packing features in a series of aryl substituted ethyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates

Cited by 27 publications

References 29 publications

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

Antimosquito Properties of 2-Substituted Phenyl/benzylamino-6-(4- chlorophenyl)-5-methoxycarbonyl-4-methyl-3,6-dihydropyrimidin-1-ium Chlorides Against Anopheles arabiensis

The CH/π Hydrogen Bond: Implication in Crystal Engineering

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