Design, antihuman immunodeficiency activity and molecular docking studies of synthesized 2-aryl and 2-pyrimidinyl pyrrolidines.

A series of thirty-one new compounds were synthesized and evaluated for their anti-HIV-1 and cytotoxicity activity. Of these, twelve were found to be inhibitors of HIV replications in primary human lymphocytes with median effective concentration (EC50) values < 20 µM. However, most of the compounds demonstrated cytotoxicity in different cells. Our structure activity relationship study identified different patterns. In the series of 2-aryl pyrrolidines, comparing the activity of the compounds containing 2-aryl substituents we observed that compounds 1c, 1f-j, 2f,g with benzyloxyphenyl and isopropoxy groups were more potent. Compounds 1g-j, 2f,g, in which the 1-aryl moiety contained a methyl group in 3,5- or 4-positions also showed high activity. In the series of compounds containing the amide, aminomethyl and nitrile groups we observed an increase in activity with C(O)NH2 < CH2NH2 < CN. In the series of 2-pyrimidinyl pyrrolidines, the best results were demonstrated with derivatives 5e and 5f, in which the presence of a benzyl fragment in 1st and aniline fragment in 6th positions of pyrimidine ring we observed an increase in anti-HIV activity. Molecular docking studies of synthesized compounds with HIV-1 reverse transcriptase enzyme were performed. Binding energies of ligands were estimated, and the interacting amino acids of HIV-1 reverse transcriptase protein were shown. Based on corroborative results of the molecular docking studies and in vitro experiments, we suggest that three groups of synthesized ligands (1c, 1f-i), (2f,g), (5e,f, 7) are of high interest for further research on new drugs against HIV. General structure of synthesized 2-aryl and 2-pyrimidinyl pyrrolidines.

Anti-human immunodeficiency activity of novel 2-arylpyrrolidine analogs.

A series of 26 new compounds were synthesized and screened for their anti-human immunodeficiency virus-1 and cytotoxicity activity. Of these, 14 were found to be inhibitors of human immunodeficiency virus replications in primary human lymphocytes with 50 % effective concentration values <20 µM. Moreover, most of the compounds were cytotoxic to human lymphocytes, CEM, and Vero cells. Our structure activity relationship study identified different patterns. Compounds 2g-j and 4 (whose structure is closer to the loviride structure) were very potent. Comparing the activity of the compounds containing the 2-aryl substituents, we observed that compounds with benzyloxyphenyl groups were more potent. Compounds in which the 1-aryl moiety contained methyl group in 4- or 3,5-positions also showed high activity. In the series of compounds containing the nitrile, amine, and amide groups, we observed a decrease in activity with CN > NH2 > C(O)NH2. The difference of activity between the 5-membered and 4-membered rings compounds was not significant. This initial information could be used to design improved anti-human immunodeficiency virus compounds in this class.

1,2,5-Substituted derivatives of 2-phenylpyrrolidine.

The structures of the potential anti-human-immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTI) 1-tert-butoxycarbonyl-2-phenylpyrrolidine-2-carboxylic acid, C(16)H(21)NO(4), (I), and 2-ammoniomethyl-1-benzyl-5-oxo-2-phenylpyrrolidine chloride, C(18)H(21)N(2)O(+).Cl(-), (II), have been investigated by X-ray diffraction. The investigations confirm a butterfly-like conformation for both compounds. In (I), the pyrrolidine ring has a marked half-chair conformation, while it has a weakly pronounced envelope conformation in (II). Intermolecular hydrogen bonds, viz. O-H.O in (I), and N-H.O and N-H.Cl in (II), build infinite chains in both structures. Rotational disorder of the three methyl groups is observed in (I).

1-Substituted derivatives of 2-phenylpyrrolidine-2-carboxamide.

The structures of two potential anti-human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTI), namely 1-(2-chlorobenzoyl)-2-phenylpyrrolidine-2-carboxamide, C(18)H(17)ClN(2)O(2), and 1-(2-furoyl)-2-phenylpyrrolidine-2-carboxamide, C(16)H(16)N(2)O(3), have been investigated by X-ray diffraction and the butterfly-like conformation established in each case. The pyrrolidine ring has the same half-chair conformation in both structures.

1-Substituted derivatives of 2-aryl-5-oxopyrrolidine-2-carboxylic acid.

The structures of two potential anti-human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTI), namely 1-benzyl-5-oxo-2-phenylpyrrolidine-2-carboxamide, C(18)H(18)N(2)O(2), (III), and 2-(4-isopropoxyphenyl)-5-oxo-1-(4-tolyl)pyrrolidine-2-carbonitrile, C(21)H(22)N(2)O(2), (IV), have been investigated by X-ray diffraction, confirming the butterfly-like conformation of both compounds. The pyrrolidine ring is in an envelope conformation in (III) and a half-chair conformation in (IV). Two intermolecular N[bond]H...O hydrogen bonds are present in the crystal structure of (III), with N...O distances of 2.995 (2) and 2.927 (2) A.