Design and Synthesis of Pyrrolidine-5,5-trans-lactams (5-Oxohexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 2. Potency and Chirality

Abstract

The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

“…77,79 Sulfonamide-based antivirals were also recently designed against the HCMV protease. 80 In contrast to the HIV PR discussed earlier, this enzyme belongs to the serine PR family, and together with similar proteases isolated from other herpes viruses, it is characterized by a particular catalytic triad, of the type His, His, Ser within the active site. 81 It was observed that a-methylpyrrolidine-5,5-trans-lactam derivatives of type 80 act as mechanism-based inhibitors of the HCMV dAla protease, acylating reversibly and in a timedependent manner the active site nucleophile Ser 132.…”

“…Compounds of type 82 bind to this PR with the 6-Me group within the S 1 subsite, the N-4-cyclopropylcarbonyl moiety within the S 1 0 subsite and the bulky, hydrophobic arylsulfonylpyrrolidine-2-carbonyl moiety within the S 3 subsite. 80 Derivatives incorporating the dansyl-(S)-proline moiety in this position showed the best activity (IC 50 of 0.34 mM) and also specificity over related serine proteases (such as elastase, thrombin, or acetyl cholinesterase), which were inhibited with IC 50 values in the range of 10-200 mM.…”

“…81 It was observed that a-methylpyrrolidine-5,5-trans-lactam derivatives of type 80 act as mechanism-based inhibitors of the HCMV dAla protease, acylating reversibly and in a timedependent manner the active site nucleophile Ser 132. 80 This serine PR hydrolyzes peptide bonds of the type Ala-Ser. Compounds of type 82 bind to this PR with the 6-Me group within the S 1 subsite, the N-4-cyclopropylcarbonyl moiety within the S 1 0 subsite and the bulky, hydrophobic arylsulfonylpyrrolidine-2-carbonyl moiety within the S 3 subsite.…”

Ammonia synthons for the multicomponent assembly of complex γ-lactams

“…We ultimately focused on two types of functionalization: acylation (including phosphonylation and sulfonylation) and arylation. Additional possible N-functionalization reactions of a related bicyclic substrate have been summarized in the work of Borthwick et al (33).…”

Phthalic Acid: A Green, Biodegradable and Environmentally Benign Nature Di-Functional Brønsted Acid Catalyst for the One-Pot Synthesis of 3, 4-Dihydropyrimidin-2- (1h)-One Derivatives and Substituted Dihydro-2-Oxypyrroles

“…Organic compounds containing nitrogenheterocyclic rings are important compounds in medicinal chemistry. Recently, because of their specially pharmaceutical and biological activities, compounds with pyrrole rings such as dihydro-2-oxypyrroles and Biginelli [5] reactions for the synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones derivatives have attracted much interest in the organic researches for example these compounds have been used as anticancer [6], calcium channel blockers, α-1a-antagonists [7], human cytomegalovirus ( HCMV) protease [8], they has been used as Pl-091 [9], many of number alkaloids with biological activities have pyrrole rings [10], And these rings have been used as UCS1025A [11]. In the recent years, several protocols for the preparation of these compounds that is including bronsted or lewis acid catalysts have been reported for example Cu(OAc) 2 [12], [Btto][p-TSA] [13], bakers , yeast [14], Calcium Fluoride [15], copper(II) tetrafluoroborate [16], hydrotalcite [17], TBAB [18], hexaaquaaluminium(III) tetrafluoroborate [19], copper(II)sulfamate [20], I 2 [21], AcOH [22], [n-Bu 4 3 [24], oxalic acid [25], ZrCl 4 [26], InCl 3 [27].…”