Bis-hydrophobic 5-(1,2-dithiolan-3-yl)pentanamide budding leads targeting brain sigma-1 receptors

Rafael Flores; Kapembwa Musenda; Deyse Brito Barbosa; Kwan H. Cheng; Donald Sikazwe

doi:10.1371/journal.pone.0352906

Abstract

Multi-mechanistic sigma-1 (σ1) receptors are implicated in several neurodegenerative pathologies including Alzheimer's disease (AD). As part of an ongoing effort to create a collection of diverse, readily synthesizable, σ1 acting small molecules for anti-neurodegenerative applications, we opted to try lipoic acid (LA) derived amides. These amides are designated as “5-(1,2 dithiolan-3-yl)pentanamides” throughout this publication. Our design approach was σ1 pharmacophore based – that is, ligands possessing three key functionalities (a hydrophobic dithiolane group, a flexible amide H-bonding linker, a hydrophobic alkyl/aryl group). Twenty-one dithiolane pentanamides were therefore designed, docked, synthesized, and pharmacologically assessed for σ1/σ2 binding affinities. Compounds 2, 6, 17 possessed promising selective σ1 binding affinities (with respective Ki values of 256, 133 and 32 nM) versus the standard ligand PD144418 (Ki = 0.08 nM). The three compounds will be used as leads in follow-up structure activity optimizations.

Citation: Flores R, Musenda K, Barbosa DB, Cheng KH, Sikazwe D (2026) Bis-hydrophobic 5-(1,2-dithiolan-3-yl)pentanamide budding leads targeting brain sigma-1 receptors. PLoS One 21(8): e0352906. https://doi.org/10.1371/journal.pone.0352906

Editor: Javed Iqbal, University of Sahiwal, PAKISTAN

Received: January 23, 2026; Accepted: June 16, 2026; Published: August 10, 2026

Copyright: © 2026 Flores et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: Principle Investigator: DS (Donald Sikazwe) Grant: SC3GM140980 Funders: National Institute of Health (NIH)/National Institute of General Medical Sciences (NIGMS) URL: https://www.nigms.nih.gov/ Funders did no play any role in this lab. research or manuscript writing.

Competing interests: The authors have declared that no competing interests exist.

1 Introduction

Gap: disease-targeted therapeutic (DTT) small molecules capable of modifying or significantly slowing AD progression are still clinically unavailable. Unabated, AD remains as an intractable progressive neurodegenerative plague that is poised to debilitate >150 million people by 2050 globally [1]. Due to the multi-factorial nature of AD, multi-mechanistic druggable targets seem to offer the opportunity to discover novel therapeutic single molecules capable of disrupting key cascades involved in disease progression. In search of central nervous system (CNS) druggable targets against AD, we decided on multi-mechanistic σ1 chaperone receptors [2]. Broadly, when σ1 receptors are activated, they bind to a diverse set of substrate proteins (ion channels included) and modify downstream signaling to yield neuronal protection in neurodegenerative disorders. In this contribution, our rationale for pursuing σ1 ligands is largely supported by such experimental evidence as: σ1 exhibits low receptor/biomarker expression densities in cognitive brain centers (prefrontal cortex, hippocampus, etc.) in early AD, σ1 agonists restored memory in AD animals and provided neuroprotection, and that σ1 activation yields anti-amnesic effects as well as stimulates synaptic plasticity [1–4]. As characterized in literature, σ1 receptors are 223 amino acid intra-mitochondria endoplasmic reticulum (ER) peptides with multi-functional signaling/neuroprotective roles [anti-inflammatory, anti-apoptosis, mitigating against reactive oxygen species (ROS) levels, increasing autophagy, β-amyloid (Aβ) plaque reduction, Ca²⁺ excitotoxicity modulation, etc.] [4–7]. To date, ligands like Blarcamesine or ANAVEX®2-73 (a σ1 agonist/M2 antagonist) have yielded promising AD clinical trials data [8,9]. Curiously, multiple central nervous system (CNS) active drugs (anti-depressants, cholinesterase inhibitors, opioids, anti-psychotics, etc.) possess σ1 activity and are being revisited for anti-neurodegenerative effects [10,11]. We therefore designed/synthesized LA based σ1 ligands to possess enhanced hydrophobic binding interactions and blood brain barrier (BBB) penetrant logP values ≥2. Our molecules feature a common dithiolane – amide motif substituted with a sampling of electronically/conformationally disparate alkyl/aryl functionalities (available in our laboratory inventory at the time, for exploratory medicinal chemistry). Secondarily, even though we were less focused on the anti-ROS aspects of the derivatives, LA’s dithiolane antioxidant properties are worth mentioning because this can be a synergistically beneficial mechanism. Essentially, under physiological conditions the dithiolane moiety equilibrates as oxidized/cyclized LA and reduced/open ring metabolite dihydrolipoic acid (DHLA, Fig 1), and both molecules are known direct/indirect antioxidants [12]. It is further indicated that the antioxidant/anti-inflammatory properties partly reside in LA’s chelation of Zn, Pb, and Cu plus the more robust DHLA’s complexation with Fe, Zn, Hg, Pb, and Cu [13,14]. Interestingly, the metal hypothesis of AD implicates Al, Fe, Zn, and Cu imbalances as contributory factors [15].

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Fig 1. LA and DHLA redox.

Physiological redox equilibration of LA and DHLA by lipoamide dehydrogenase, glutathione reductase, and thioredoxin reductase [12,16].

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This manuscript shares aspects of design, synthesis, and σ1 pharmacological binding affinities of twenty-one hydrophobic 5-(1,2-dithiolan-3-yl)pentanamides. Design considerations included structural adherence to the reported σ1 ligand’s pharmacophore illustrated in Fig 2 [17]. This pharmacophore proposes that σ1 ligand’s chemical basis of action is related to their ability to form a minimum of two hydrophobic and one H-bonding interactions within receptor’s active site [17].

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Fig 2. Sigma 1 ligands pharmacophore.

The σ1 “hydrophobic/H-bond linker/hydrophobic” pharmacophore model represented by the dithiolane/flexible amide linker/alkyl or aryl R-substituents in the target compounds. The flexible amide linker, which is amenable to chain length variation and conformational constraint, will be explored in future structure activity relationship (SAR) studies of our three leads.

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Additionally, all target compounds were computationally evaluated for σ1 receptor binding affinity, active site interactions, and drug-likeness [per Lipinski’s rule of five” or RoF, plus absorption/distribution/metabolism/elimination (ADME) attributes], prior to synthesis [18,19]. All synthesized compound structures were confirmed using proton (¹H) and carbon (¹³C) nuclear magnetic resonance (NMR) experiments, and high-resolution mass spectrometry (HR-MS) analysis. In vitro σ1/σ2 receptor binding affinities are also determined for all compounds.

2 Results and Discussion

2.1 Synthesis

Designed/modelled pentanamides were conveniently synthesized in parallel, using slightly modified one-pot amidation conditions. Synthesis was achieved through direct coupling reactions between LA [also called “5-(1,2-dithiolan-3-yl)pentanoic acid”] and appropriate alkyl-/aryl-amines, aided by either “1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU)” or “1,1’-carbonyldiimidazole (CDI)” (Scheme 1) [20,21]. The ensuing twenty-one target compounds are indicated in Fig 3.

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Fig 3. Compound structures.

Twenty-one target compounds CAS SciFinder^® searches revealed that compounds 5, 8-13, 15, 16, 18-21 are new, while 1-4, 6, 7, 14, 17 are known and reported elsewhere for disparate applications [22–29]. Componds 2, 6, 17 exhibited promising selective in vitro binding affinities at σ1.

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Scheme 1. One-step amidation using either HATU (1a, diisopropylethylamine or DIPEA in dimethylformamide or DMF) or CDI (1b, in tetrahydrofuran or THF) coupling conditions.

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2.2 Docking simulations

The protein data bank (PDB) yielded σ1 receptor 3D structure (i.e., PDB ID: 5HK1 plus crystallographic ligand: PD144418) [30]. Removal of H₂O and crystallization artifacts from the 3D structure were achieved with Pymol and Gasteiger-Huckel, charges were added together with hydrogen atoms to optimize their hydrogen bonds [31]. Conformational searches and scoring were performed based on the crystallographic ligand interaction locations. Scoring functions were obtained via the Autodock Vina 1.1.2 platform [32]. The search area was delineated by Autodock Tools 1.5.7 program, by defining a box with x = 12 Å; y = 12 Å; and z = 16 Å dimensions [33]. Table 1 indicates the predicted affinity scores (kcal/mol) for our compounds versus the high affinity reference σ1 ligand PD144418. Lower or more negative free energy (kcal/mol) scores suggest higher binding affinities.

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Table 1. Autodock Vina binding scores (kcal/mol) for compounds 1 - 21 and PD144418. In vitro promising molecules (2, 6, 17) exhibited low to comparable predicted affinity scores versus PD144418.

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Interaction maps (Figs 4–6) of the three promising leads (compounds 2, 6, 17) were generated using Discovery Studio Visualizer [34].

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Fig 4. Compound 2’s interactions map.

Bonding interaction map of 2 at σ1 active site. Interactions were colored using the following scheme: van der Waals (light green); conventional hydrogen bonds (bright green); π-donor or carbon hydrogen bonds (pale green); π-anion/attractive charge interactions (orange); π-sigma (purple); π-sulfur (yellow); π-π stacked and π-π T-shaped interactions (magenta); and alkyl/π-alkyl interactions (light pink).

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Fig 5. Compound 6’s interactions map.

Interaction map of compound 6 at σ1 active site. The interaction color scheme is as described for Fig 4.

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Fig 6. Compound 17’s interactions map.

Interaction map of 17 at σ1 active site. Fig 4 interaction color scheme applies here as well.

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Compound 2 (predicted affinity score = −7.4 kcal/mol) aromatic imidazole establishes three different pi-bonds (π-bonds): π-anion with Asp126, π-stacking with His154 and π-alkyl with Ile124. The carbonyl group hydrogen bonds (H-bonds) with Tyr120, and the dithiolane ring alkylates with Met93, Tyr103, Leu105, and Ala185. Additionally, several hydrophobic interactions can be established along the ligand extension, with residues as Val84, Trp89, Phe107, Ser117, Phe133, Val152, Val162, Trp164, Glu172 and Leu182.

Molecule 6 (score = −9.0 kcal/mol) bonds to σ1 via dithiolane alkyl/Leu105/Ala185 and π-sulfur interaction with Tyr103. Additionally, the alkyl linker establishes alkyl interactions with Val84, Met93, and Leu105. H-bonds occur between the carbonyl oxygen and Tyr120, and between the imidazole amine and Glu172. The benzimidazole group π-bonds to Trp89, Asp126, His154, and Glu172. Hydrophobic interactions are observed with residues Leu95, Phe107, Ser117, Ile124, Phe133, Val162, Trp164, Thr181, Leu182, and Phe184.

High affinity compound 17 (score = −9.7 kcal/mol) establishes benzyl ring π-bonds with Leu95, Tyr103, Leu182, and Tyr206. The dithiolane group forms alkyl interactions with Ile124, His154 and Val162, while the charged nitrogen interacts with Glu172. Val84, Trp89, Tyr120, Met93, Tyr103, Leu105, Phe107, Ser117, Asp126, Phe133, Trp164, Ile178, Thr181, and Ala185 participate in hydrophobic bonding.

Overall, prior studies involving high-affinity inhibitors described residues Tyr103 and Glu172 as being fundamental to σ1 inhibition [30]. In this study, ligands capable of establishing stronger interactions with these residues also exhibited more favorable predicted binding affinity scores. Our interaction profile suggested that compounds capable of forming electrostatic interactions with Glu172 and H-bonds with Tyr103 exhibited more favorable binding energies. Conversely, ligands interacting mainly through van der Waals contacts with the same residues showed comparatively weaker predicted affinities. The interaction maps and affinity scores also suggested a correlation between in vitro activity and predicted binding affinities, meaning that increased biological activity was related to lower docking scores.

2.3 Drug likeness

Drug likeness molecular filters are plentiful, and they all attempt to indicate the prevalence of substructures among marketed drug molecules [35]. Lipinski’s RoF oral drug-like filters are mostly related to the compound’s molecular weight (MW), lipophilicity (i.e., calculated log octanol/water coefficient or ClogP values), H-bond donors (HBDs) and H-bond acceptors (HBAs) [17,36]. Alternatively, the multiparameter optimization (MPO) algorithm considers MW, ClogP, calculated log distribution (ClogD, pH = 7.4) coefficient, topological polar surface area (TPSA), HBDs, and pKa as drug likeness filters for CNS molecules [37]. Moreover, H₂O solubility (logS) is also an important parameter, it influencesdrug absorption and distribution…low H₂O solubility implies variable to poor drug oral bioavalability.We deployed the open-source SwissADME pharmacokinetic tool to predict some of the above indicated attributes plus Cyp450 enzyme disposition early in drug design, prior to undertaking any chemical synthesis [19]. The main reasons for using SwissADME were ease of accessibility and multi-parametric robustness. Illustrated in Table 2 are molecular weight (MW), consensus ClogP values, TPSA, and drug-likeness (Dl) scores of our target compounds. Complete SwissADME predicted pharmacokinetic properties for the individual compounds are listed in S1 File.

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Table 2. This table displays compound MWs and sample SwissADME generated pharmacokinetic scores including “drug-likeness.”.

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Our compounds met the Lipinski RoF guidelines [MWs < 500, HBDs (NH/OH ≤ 5 moieties) and HBAs (O/N ≤ 10 atoms), calculated logPs < 5, etc.]. Ostensibly, lipophilic small MW molecules have enhanced chances of traversing endothelial cells of the blood brain barrier (BBB) [38]. Apart from 15 (ClogP = 0.9), the rest of the molecules possessed moderate to highly lipophilic (ClogP values 1.6–4.5). In fact, compound 17, with a CLogP = 3.75 and 83Å² TPSA, has good brain penetrant potential. Reportedly, TPSA ≤ 90Å² scores imply enhanced brain bioavailability [39]. According to the “organic chemistry portal (https://www.organic-chemistry.org/prog/peo/logS.html),” most of our compounds fell in the very to moderate H₂O solubility range of most marketed drugs (SwissADME S1 File).

2.4 Receptor binding affinities

Compound affinity experiments (σ1/σ2 K_i values) were conducted by the “National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH PDSP)”, at University of North Carolina (UNC) Chapel Hill, NC. Protocol details of the competitive radioligand displacement assays utilized are reported elsewhere [40]. Table 3 below indicates the K_i values for all compounds.

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Table 3. The binding affinity (Ki) data set at both σ1 and σ2. Molecules 2, 6, 17 exhibited the best and selective saturation radioligand affinities for σ1. Notably, PD144418 binding affinity for σ1 is exceptionally high hence its use as a comparator ligand [41]. ND = Not Determined (>10,000 nM activity).

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3 Conclusion

Twenty-one derivatives were successfully designed based on the “hydrophobic pharmacophore” concept, modelled (via affinity scores, for active site interactions, and for ADME), synthesized, and characterized (by NMR and HRMS). Derivatives were tested in vitro for binding affinities at σ1/σ2. Compounds 2, 6, 17 structures were well accommodated within σ1 active site and established multiple van der Walls interactions with residues around the gorge – an indicator of stable binding. SwissADME calculations indicated that the derivatives were lipophilic and drug-like. Additionally, 2, 6, 17 exhibited respective selective in vitro affinities of 255, 133, 31 nM (Ki values) at σ1. Thusly, the three compounds are promising leads for future structure optimization research on LA inspired hydrophobic σ1 ligands.

4 Experimental

4.1 General

Synthetic chemicals were sourced from several vendors (Thermo Fisher Scientific, Millipore Sigma, etc.) and used in the purity (>95%) received. Melting points were obtained using the “Mel-temp” instrumentand reported as uncorrected values. Product purifications were conducted using the “Teledyne Combiflash Rf” flash chromatography. “Silica Gel 60 F₂₅₄ TLC plates” were utilized for monitoring reaction progress using either the hexanes/ethylacetate (7:3) or dichloromethane/methanol (9:1) co-solvents. Compound spectra (¹H/¹³C) were obtained using Bruker 300 MHz NMR spectroscopy (deuterated DMSO-d₆ or CDCl₃ solvents). Chemical shifts ¹H/¹³C are reported versus Tetramethylsilane (TMS or SiMe₄) internal standard. Structural data are reported as “chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (J in Hz), proton numbers, and mass to charge ratio” (S2 File). HR-MS data were collected on a “maXis plus quadrupole-time of flight mass spectrometer equipped with an electrospray ionization source (Bruker Daltonics),” in positive ionization mode (S3 File). HR-MS experiments were conducted by the Univ. of Texas at San Antonio (UTSA) Mass Spectrometry & Proteomics Core Facility.

4.2 Chemistry

HATU coupling procedure (A). A mixture of (R/S)-lipoic acid (1 eq), HATU (1.2 eq), the appropriate alkyl-/aryl-amine (1.2 eq), dimethylformamide (DMF) was stirred in a round bottom (RB) flask, under N₂. Diisopropylethylamine (DIPEA, 2.2 eq) was then injected dropwise and reaction progress was monitored by thin layer chromatography (TLC). After 24 hours, the reaction mixture was diluted with 15 mL of dichloromethane (DCM), successively washed with deionized water (3 X 20mL) and extracted with DCM (3 X 20mL). Organic extracts were combined, dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by flash chromatography (Combi-Flash Rf) using either ethyl acetate using hexane/ethyl acetate (7:3) or DCM/MeOH (9:1) gradient solvent systems.

CDI coupling procedure (B). The appropriate alkyl-/aryl-amine (1.1 eq) was added in one portion to a cooled RB flask charged with (R/S)-lipoic acid (1 eq), 1,1’-Carbonyldiimidazole (CDI, 1.2 eq), in tetrahydrofuran (THF), under N₂, and stirred. Reaction progress was monitored over 24 hours by TLC. Solvent was evaporated, and the oily product mixture was diluted with water (15 mL) then extracted with DCM (3 X 15 mL). Combined organic phases of the crude product were dried over Na₂SO₄ and purified by Combi-Flash Rf, using either ethyl acetate using either hexane/ethyl acetate (7:3) or DCM/MeOH (9:1) as gradient eluent solvents.

4.3 Synthetic specifics and spectral data

[Methyl 4-((5-(1,2-dithiolan-3-yl)pentanamido)methyl)benzoate] (1) [22]: (R/S)-lipoic acid (R/S-LA) (500 mg, 2.4 mmol) was reacted with methyl 4-(aminomethyl) benzoate hydrochloride (587 mg, 2.9 mmol) and DIPEA (870 µL, 5 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (1.1 g, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish crystalline solid. (658 mg), yield: 77%; mp: 100−102 ℃; ¹HNMR(300 MHz, DMSO-d₆): δ 8.44 (t, J = 5.96 Hz 1H, NH), δ 7.92 (d, J = 8.31 Hz, 2H, CH Ar), δ 7.37 (d, J = 8.32 2H, CH Ar), δ 4.33 (d, J = 5.96, 2H, CH₂), δ 3.84 (s, 3H, CH₃), δ 3.67–3.55 (m, 1H, CH₂), δ 3.24–3.06 (m, 2H, CH₂), δ 2.46–2.34 (m, 1H, CH), δ 2.17 (t, J = 7.20 Hz, 2H, CH₂), δ 1.93–1.79 (m, 1H, CH) δ 1.74–1.47 (m, 4H, 2CH₂), δ 1.43–1.28 (m, 2H, CH₂); ¹³CNMR (300 MHz, CDCl₃): 172.6670, 166.8073, 143.5963, 130.0277, 129.3613, 127.5786, 56.4007, 52.1523, 43.2173, 40.2500, 38.4862, 36.4009, 34.6082, 28.8859, 25.3570; HRMS (ESI) m/z calcd. for C₁₇H₂₃NO₃S₂ [(M + H)⁺] 354.1192, found 354.1190.

[N-(2-(1H-imidazol-4-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamide] (2) [23,30]: R/S-LA (309 mg, 1.5 mmol) was reacted histamine dihydrochloride (326 mg, 1.8 mmol) and DIPEA (1mL, 5.4 mmol) in DMF (5 mL) at room temperature for 24 h with HATU (698 mg, 1.8 mmol) as the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish crystalline solid. (170 mg), yield: 24%; mp: 99−101 ℃; ¹HNMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H, NH), δ 7.85 (s, 1H, NH), δ 7.51 (s, 1H, CH Ar), δ 6.84–6.65 (m, 1H, CH Ar), δ 3.60 (m, 1H, CH), δ 3.30–3.07 (m, 4H, 2CH₂), δ 2.75–2.54 (m, 2H, CH₂), δ 2.48–2.35 (m, 1H, CH), δ 2.05 (t, J = 7.24 Hz, 2H, CH₂), δ 1.93–1.80 (m, 1H, CH), δ 1.74–1.44 (m, 4H, 2CH₂), δ 1.42–1.25 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 172.2558, 135.0466, 56.5985, 38.5690, 35.7060, 34.5980, 28.7620, 27.5202, 25.5169; HRMS (ESI) m/z calcd. for C₁₃H₂₁N₃OS₂ [(M + H)⁺] 300.1199, found 300.1196.

[N-(benzo[d] [1,3]dioxol-5-ylmethyl)-5-(1,2-dithiolan-3-yl)pentanamide] (3) [24]: R/S-LA (500 mg, 2.4 mmol) was reacted with piperonylamine (440 mg, 2.9 mmol) and DIPEA (1.3 mL, 7 mmol) in THF (10 mL) at room temperature for 24 h with CDI (470 mg, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish crystalline solid. (362 mg), yield: 44%; mp: 84−87 ℃; ¹HNMR (300 MHz, DMSO-d₆): δ 8.24 (t, 1H, NH), δ 6.83 (t, 2H, 2CH Ar), δ 6.71 (m, 1H, CH Ar), δ 5.98 (s, 2H, CH₂), δ 4.15 (d, J = 5.93 Hz, 2H, CH₂), δ 6.37–3.54 (m, 1H, CH), δ 3.24–3.05 (m, 2H, CH₂), δ 2.47–2.34 (m, 1H, CH), δ 2.12 (t, J = 7.29 Hz, 2H, CH₂), δ 1.92–1.78 (m, 1H, CH), δ1.74–1.46 (m, 4H, 2CH₂), δ 1.43–1.23 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 172.3171, 147.6776, 146.4375, 134.1199, 120.8179, 108.4243, 108.3237, 101.2513, 56.5913, 42.2392, 38.5715, 35.6051, 34.5649, 28.7664, 25.5120; HRMS (ESI) m/z calcd. for C₁₆H₂₁NO₃S₂ [(M + H)⁺] 340.1036, found 340.1032.

[5-(1,2-dithiolan-3-yl)-N-(2-(pyridin-3-yl)ethyl)pentanamide] (4) [25]: R/S-LA (500 mg, 2.4 mmol) was reacted with 3-(2-aminoethyl)pyridine (350 µL, 2.9 mmol) and DIPEA (840 µL, 4.6 mmol) in THF (10 mL) at room temperature for 24 h with CDI (470 mg, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish crystalline solid. (380 mg), yield: 50%; mp: 53−56 ℃; ¹HNMR (300 MHz, DMSO-d₆): δ 8.42 (m, 2H, CH Ar), δ 7.89 (m, 1H, NH), δ 7.62 (m, 1H, CH Ar), δ 7.35–7.27 (m, 1H, CH Ar), δ 3.65–3.53 (m, H, CH), δ 3.34–3.07 (m, 4H, CH₂), δ 2.72 (t, J = 6.97 Hz, 2H, CH₂), 2.47–2.35 (m, 1H, CH), δ 2.03 (t, J = 7.29 Hz, 2H, CH₂), δ 1.93–1.78 (m, 1H, CH), δ 1.72–1.40 (m, 4H, 2CH₂), δ 1.38–1.20 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 172.3717, 150.3380, 147.8308, 136.6230, 135.4389, 123.8265, 56.5837, 38.5767, 35.6485, 34.5931, 32.6615, 28.7346, 25.497; HRMS (ESI) m/z calcd. for C₁₅H₂₂N₂OS₂ [(M + H)⁺] 311.1246, found 311.1243.

[N-(benzo[d]oxazol-2-yl)-5-(1,2-dithiolan-3-yl)pentanamide] (5): R/S-LA (500 mg, 2.4 mmol) was reacted with 2-Aminobenzoxazole (390 mg, 2.9 mmol) and DIPEA (840 µL, 4.6 mmol) in DMF (10 mL) at room temperature for 24 h. HATU (1.1g, 2.9 mmol) was the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish crystalline solid. (251 mg), yield: 32%; mp: 109−111 ℃; ¹HNMR(300 MHz, DMSO -d₆): δ 11.60 (s, 1H, NH), δ 7.64–7.54 (m, 2H, 2CH Ar), δ 7.36–7.21 (m, 2H, 2CH Ar), δ 3.71–3.58 (m, 1H, CH), δ 3.26–3.04 (m, 2H, CH₂), δ 2.57–2.35 (m, 3H, CH₂ CH), δ 1.97–1.81 (m, 1H, CH), δ 1.79–1.52 (m, 4H, 2CH₂) δ 1.50–1.34 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 171.2725, 155.5937, 148.0528, 141.1830, 124.9585, 123.9179, 118.6209, 110.4518, 56.5256, 40.3799, 38.5954, 36.1424, 34.5871, 28.6218, 24.6285; HRMS (ESI) m/z calcd. for C₁₅H₁₈N₂O₂S₂ [(M + H)⁺] 323.0882, found 323.0877.

[N-(1H-benzo[d]imidazol-2-yl)-5-(1,2-dithiolan-3-yl)pentanamide] (6) [26]: R/S-LA (500 mg, 2.4 mmol) was reacted with 2-Aminobenzoxazole (400 mg, 2.9 mmol) and DIPEA (1 mL, 5.4 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (1.1g, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish crystalline solid (350 mg), yield: 45%; mp: 217−219 ℃; ¹HNMR(300 MHz, DMSO-d₆): δ 12.03 (s, 1H, NH), δ 11.48 (s, 1H, NH), δ 7.43 (s, 2H, 2CH Ar), δ 7.12–7.02 (m, 2H, 2CH Ar), δ 3.71–3.58 (m, 1H, CH), δ 3.26–3.07 (m, 2H, CH₂), δ 2.50–2.35 (m, 3H,CH CH₂), δ 1.96–1.81 (m, 1H, CH), δ 1.80–1.52 (m, 4H, 2CH₂), δ 1.50–1.35 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 172.8391, 147.0740, 121.3321, 56.5259, 40.3861, 38.5882, 35.7100, 34.5913, 28.6689, 24.9987, HRMS (ESI) m/z calcd. for C₁₅H₁₉N₃OS₂ [(M + H)⁺] 322.1042, found 322.1037.

[5-(1,2-dithiolan-3-yl)-N-(4-sulfamoylbenzyl)pentanamide] (7) [27]: R/S-LA (500 mg, 2.4 mmol) was reacted with 4-(Aminomethyl)benzenesulfonamide hydrochloride (643 mg, 2.9 mmol) and DIPEA (1 mL, 5.4 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (1.1g, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish solid (580 mg), yield: 64%; mp: 114−117 ℃; ¹HNMR(300 MHz, DMSO-d₆): δ 8.42 (t, J = 5.87 Hz, 1H, NH), δ 7.77 (d, J = 8.25 Hz, 2H, 2CH Ar), δ 7.41 (t, J = 8.34 Hz,2H, 2CH), δ 7.32 (s, 2H, NH₂), δ 4.32 (d, J = 5.96 Hz, 2H, CH₂), δ 3.68–3.55 (m, 1H, CH), δ 3.25–3.07(m, 2H, CH₂), δ 2.47–2.35 (m, 1H, CH), δ 2.16 (t, J = 7.29 Hz, 2H, CH₂), δ 1.93–1.80 (m, 1H, CH), δ 1.76–1.48 (m, 4H, 2CH₂), δ 1.45–1.29 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 172.6110, 144.3358, 143.0168, 127.9082, 126.1365, 56.5922,42.1196, 40.3884, 38.5944, 35.5842, 34.5887, 28.7991, 25.4739; HRMS (ESI) m/z calcd. for C₁₅H₂₂N₂O₃S₃ [(M + H)⁺] 375.0865, found 375.0858.

[N-(4,5-dimethylthiazol-2-yl)-5-(1,2-dithiolan-3-yl)pentanamide] (8): R/S-LA (500 mg, 2.4 mmol) was reacted with 2-Amino-4,5-dimethylthiazole hydrochloride (440 mg, 2.7 mmol) and DIPEA (600 µL, 3.6 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (1.1g, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish solid (133 mg), yield: 25%; mp: 108−110 ℃; ¹HNMR(300 MHz, CDCl₃): δ 10.70 (s, 1H, NH), δ 3.63–3.48 (m, 1H, CH), δ 3.25–3.05 (m, 2H, CH₂), δ 2.53–2.37 (m, 3H, CH CH₂), δ 2.31 (s, 3H, CH₃), δ 2.25 (s, 3H, CH₃), δ 1.97–1.82 (m, 1H, CH), δ 1.82–1.60 (m, 4H, 2CH₂), δ 1.59–1.38 (m, 2H, CH₂), ¹³CNMR, δ (ppm) (300 MHz, DMSO-d₆): 171.0700, 154.0563, 141.9496, 118.6859, 56.4994, 40.3719, 38.5884, 35.1804, 34.5280, 28.6640, 24.9946, 14.7479, 10.7797; HRMS (ESI) m/z calcd. for C₁₃H₂₀N₂OS₃ [(M + H)⁺] 317.0811, found 317.0807.

[N-(2-(2H-tetrazol-5-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamide] (9): R/S-LA (500 mg, 2.4 mmol) was reacted with 2-(2H-Tetrazol-5-yl)ethan-1-amine hydrochloride (407 mg, 2.7 mmol) and DIPEA (600 µL, 3.6 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (1.1g, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish solid (160 mg), yield: 22%; mp: 141−143 ℃; ¹HNMR(300 MHz, DMSO-d₆): δ 7.98 (m, 1H, NH), δ 3.67–3.54 (m, 1H, CH), 3.46–3.36 (m, 1H, CH), 3.25–3.08 (m, 3H, CH CH₂), δ 3.01 (t, J = 6.92 Hz, 2H, CH₂), δ 2.48–2.34 (m, 1H, CH), δ 2.03 (t, J = 7.29 Hz, 2H, CH₂), δ 1.92–1.79 (m, 1H, CH), δ 1.71–1.41 (m, 4H, 2CH₂), δ 1.38–1.23 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 172.6897, 154.5424, 56.5489, 40.3558, 38.5706, 37.1641, 35.5487, 34.5708, 28.6870, 25.3849, 23.9667; HRMS (ESI) m/z calcd. for C₁₁H₁₉N₅OS₂ [(M + H)⁺] 302.1104, found 302.1103.

[5-(1,2-dithiolan-3-yl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)pentan-1-one] (10): R/S-LA (352 mg, 1.7 mmol) was reacted with 2-(1-Piperazinyl)pyrimidine (306 mg, 1.9 mmol) in THF (5 mL) at room temperature for 24 h with CDI (423 mg, 2.6 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (123 mg), yield: 15%; mp: 50−53 ℃; ¹HNMR(300 MHz, CDCl₃): δ 8.26 (d, J = 4.77 Hz 2H, 2CH Ar), δ 6.48 (d, J = 4.72 Hz, 1H, CH Ar), δ 3.85–3.70 (m, 4H, 2CH₂), δ 3.69–3.59 (m, 2H, CH₂), δ 3.58–3.43 (d, 3H, CH CH₂), δ 3.18–3.00 (m, 2H, CH₂), δ 2.47–2.27 (m, 3H, CH CH₂), δ 1.93–1.79 (m, 1H, CH), δ 1.75–1.36 (d, 6H, 3CH₂); ¹³CNMR(300 MHz, CDCl₃): 171.4495, 161.4944, 157.7829, 110.4687, 56.4354, 45.3397, 43.7958, 43.5694, 41.3734, 40.2574, 38.5135, 34.7812, 33.0970, 29.1107, 24.9619; HRMS (ESI) m/z calcd. for C₁₆H₂₄N₄OS₂ [(M + H)⁺] 353.1464, found 353.1457.

[5-(1,2-dithiolan-3-yl)-N-(quinolin-3-yl)pentanamide] (11): R/S-LA (500 mg, 2.4 mmol) was reacted with 3-Aminoquinoline (419 mg, 2.9 mmol) and DIPEA (800 µL, 5 mmol) in DMF (6 mL) at room temperature for 24 h with HATU (1.1g, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “A”, as a yellowish solid (168 mg), yield: 21%; mp: 119−121 ℃; ¹HNMR (300 MHz, CDCl₃): δ 8.78 (s, 2H, 2CH Ar), δ 8.23 (s, 1H, NH), δ 8.02 (d, J = 8.34 Hz, 1H, CH Ar), δ 7.78 (d, J = 8.16 Hz 2H, 2CH Ar), δ 7.63 (m, 1H, CH Ar), δ 7.53 (m, 1H, CH Ar), δ 3.63–3.50 (s, 1H, CH), δ 3.24–3.04 (m, 2H, CH₂), δ 2.54–2.37 (m, 3H, CH CH₂), δ 1.96–1.41 (s, 7H, 3CH₂ CH); ¹³CNMR(300 MHz, CDCl₃): 171.9492, 145.0323, 143.8637, 131.6763, 128.7711, 128.4013, 128.2611, 127.8164, 127.3673, 124.0907, 56.3991, 40.2752, 38.5120, 37.2851, 34.6210, 28.8753, 25.1630, HRMS (ESI) m/z calcd. for C₁₇H₂₀N₂OS₂ [(M + H)⁺] 333.1090, found 333.1085.

[5-(1,2-dithiolan-3-yl)-N-(5-methylisoxazol-3-yl)pentanamide] (12): R/S-LA (500 mg, 2.4 mmol) was reacted with 3-amino-5-methylisoxazole (300 mg, 2.9 mmol) and DIPEA (800 µL, 5 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (1.1 g, 2.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (214 mg), yield: 31%; mp: 88−90 ℃; ¹HNMR(300 MHz, CDCl₃): δ 9.88 (s, 1H, CH Ar), δ 6.70 (s, 1H, CH Ar), δ 3.58–3.45 (m, 1H, CH), δ 3.17–2.99 (m, 2H, CH₂), δ 2.48–2.37 (m, 3H, CH CH₂), δ 2.35 (s, 3H, CH₃), δ 1.91–1.77 (m, 1H, CH), δ 1.76–1.58 (s, 4H, 2CH₂), δ 1.57–1.35 (s, 2H, CH₂); ¹³CNMR(300 MHz, CDCl₃): 171.4389, 169.9553, 158.4442, 96.6661, 56.3522, 40.2336, 38.5153, 36.7670, 34.6425, 28.8276, 24.9810,12.7245; HRMS (ESI) m/z calcd. for C₁₂H₁₈N₂O₂S₂ [(M + H)⁺] 287.0882, found 287.0880.

[5-(1,2-dithiolan-3-yl)-N-(3-phenylisoxazol-5-yl)pentanamide] (13): R/S-LA (500 mg, 2.4 mmol) was refluxed with 5-amino-3-phenylisoxazole (465 mg, 2.9 mmol) in THF (10 mL) at 66 ℃ for 24 h with CDI (589 mg, 3.6 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (98 mg), yield: 12%; mp: 90−92 ℃; ¹HNMR (300 MHz, CDCl₃): δ 8.48 (s, 1H, NH Ar), δ 7.79–7.68 (m, 2H, 2CH Ar), δ 7.38 (m, 3H, 3CH Ar), δ 6.67 (s, 1H, CH Ar), δ 3.57–3.44 (m, 1H, CH), δ 3.18–2.99 (m, 2H, CH₂), δ 2.47–2.31 (m, 3H, CH CH₂), δ 1.91–1.77 (m, 1H, CH), δ 1.76–1.55 (m, 4H, 2CH₂), δ 1.54–1.34 (m, 2H, CH₂); ¹³CNMR, δ (ppm) (300 MHz, CDCl₃): 169.2245, 163.8211, 160.6310, 130.2767, 128.9544, 126.8079, 87.1703, 56.3200, 40.2685, 38.5295, 36.4398, 34.5836, 28.7406, 24.7977; HRMS (ESI) m/z calcd. for C₁₇H₂₀N₂O₂S₂ [(M + H)⁺] 349.1039, found 349.1033.

[N'-(5-(1,2-dithiolan-3-yl)pentanoyl)-4-chlorobenzohydrazide] (14) [28]: R/S-LA (500 mg, 2.4 mmol) was refluxed with 4-chlorobenzhydrazide (496 mg, 2.9 mmol) in THF (10 mL) at 66℃ for 24 h, using CDI (589 mg, 3.6 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (340 mg), yield: 40%; mp: 182−185 ℃; ¹HNMR: δ (ppm) (300 MHz, DMSO -d₆) δ 10.40 (s, 1H, NH), δ 9.90 (s, 1H, NH), δ 7.88 (d, J = 8.53 Hz, 2H, 2CH Ar), δ 7.57 (d, J = 8.53 Hz, 2H, 2CH Ar), δ 3.69–3.54 (m, 1H, CH), δ 3.27–3.07 (m, 2H, CH₂), δ 2.49–2.35 (m, 1H, CH), δ 2.20 (t, J = 7.11 Hz, 2H, CH₂), δ 1.97–1.81 (m, 1H, CH), δ 1.78–1.50 (m, 4H, 2CH₂), δ 1.49–1.31 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 171.8851, 164.9207, 137.0721, 131.7220, 129.8137, 129.0569, 56.6141, 40.3891, 38.5659, 34.5810, 33.5649, 28.6978, 25.3074; HRMS (ESI) m/z calcd. for C₁₅H₁₉ClN₂O₂S₂ [(M + H)⁺] 359.0649, found 359.0643.

[N-(2,5-dioxopyrrolidin-3-yl)-5-(1,2-dithiolan-3-yl)pentanamide](15): R/S-LA (500 mg, 2.4 mmol) was reacted with 1-aminohydantoin hydrochloride (440 mg, 2.9 mmol) and DIPEA (1mL, 5.4 mmol) in DMF (10 mL) at room temperature for 24 h. HATU (1.1 g, 2.9 mmol) was the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (120 mg), yield: 16%; mp: 148−151 ℃; ¹HNMR(300 MHz, DMSO-d₆): δ 11.21 (s, 1H, NH), δ 10.21 (s, 1H, NH), δ 4.02 (s, 2H, CH₂), δ 4.02 (s, 2H, CH₂), δ 3.70–3.54 (m, 1H, CH), δ 3.25–3.05 (m, 2H, CH₂), δ 2.48–2.33(s, 2H, CH₂), δ 2.14 (t, J = 7.15 Hz, 2H, CH₂), δ 1.94–1.81 (m, 1H, CH), δ 1.74–1.47 (m, 4H, 2CH₂), δ 1.45–1.30 (m, 2H, CH₂); ¹³CNMR (300 MHz, DMSO-d₆): 172.3385, 170.5409, 157.8951, 56.5259, 53.1820, 40.3376, 38.5679, 34.4834, 32.9759, 28.5078, 24.9223; HRMS (ESI) m/z calcd. for C₁₁H₁₇N₃O₃S₂ [(M + Na)⁺] 326.0604, found 326.0604.

[5-(1,2-dithiolan-3-yl)-N-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)pentanamide] (16): R/S-LA (300 mg, 1.5 mmol) was reacted with 2-amino-5-(4-fluorophenyl)-1,3,4-thiadiazole (350 mg, 1.8 mmol) and DIPEA (600 µL, 3.4 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (650 mg, 1.7 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (152 mg), yield: 27%; mp: 215−218 ℃; ¹HNMR(300 MHz, DMSO-d₆): δ 12.65 (s, 1H, NH), δ 8.00 (m, 2H, 2CH Ar), 7.37 (m, 2H, 2CH Ar), δ 3.72–3.55 (m, 1H, CH), δ 3.25–3.05 (m, 2H, CH₂), δ 2.48–2.34 (m, 1H, CH), δ 1.96–1.80 (sex, J = 6.6390 Hz, 1H, CH), δ 1.78–1.50 (m, 4H, 2CH₂), δ 1.48–1.30 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 171.9448, 161.0643, 158.8594, 129.7432, 129.6270, 117.0473, 116.7547, 56.4645, 40.3704, 38.5985, 35.1675, 34.5119, 28.6078, 24.8054; HRMS (ESI) m/z calcd. for C₁₆H₁₈FN₃OS₃ [(M + H)⁺] 384.0669, found 384.0663.

[N-(1-benzylpiperidin-4-yl)-5-(1,2-dithiolan-3-yl)pentanamide] (17) [29]: R/S-LA (260 mg, 1.3 mmol) was reacted with 1-benzylpiperidine-4-amine (270 µL, 1.3 mmol) and DIPEA (500 µL, 5.2 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (608 mg, 1.6 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (68 mg), yield: 15%; mp: 79−82 ℃; ¹HNMR (300 MHz, CDCl₃): δ 7.36–7.21 (m, 5H, 5CH Ar), δ 5.32 (m, 1H, NH), 3.89–3.72 (m, 1H, CH), δ 3.63–3.52 (m, 1H, CH), δ 3.51–3.46 (s, 2H, CH₂), δ 3.23–3.06 (m, 2H, CH₂), δ 2.89–2.77 (m, 3H, CH₂), δ 2.58–2.40 (sex, J = 6.2172 Hz, 1H, CH), δ 2.22–2.01 (m, 4H, 2CH₂), δ 2.00–1.80 (m, 3H, CH₂CH), δ 1.79–1.57 (m, 4H, 2CH₂), δ 1.56–1.34 (m, 4H, 2CH₂); ¹³CNMR(300 MHz, CDCl₃): 171.9992, 138.1433, 129.1637, 128.2664, 127.1346, 63.0485, 56.4401, 52.2850, 46.4350, 40.2555, 38.4824, 36.6530, 34.6285, 32.2757, 28.8633, 25.4383; HRMS (ESI) m/z calcd. for C₂₀H₃₀N₂OS₂ [(M + H)⁺] 379.1872, found 379.1872.

[5-(1,2-dithiolan-3-yl)-N-(9H-fluoren-9-yl)pentanamide] (18): R/S-LA (300 mg, 1.5 mmol) was reacted with 9-Aminofluorene hydrochloride (380 mg, 1.8 mmol) and DIPEA (700 µL, 4.0 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (718 mg, 1.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (316 mg), yield: 59%; mp: 188−191 ℃; 1HNMR(300 MHz, DMSO-d6): δ 8.45 (d, J = 8.3447 Hz, 1H, NH), δ 7.87 (d, J = 7.3360 Hz, 2H, 2CH Ar), δ 7.53–7.38 (m, 4H, 4CH Ar), δ 7.37–7.28 (m, 2H, 2CH Ar), δ 6.04 (d, J = 8.5280 Hz, 1H, CH), δ 3.70–3.58 (m, 1H, CH), δ 3.25–3.08 (m, 2H, CH₂), δ 2.49–2.37 (m, 1H, CH), δ 2.22 (t, J = 7.1067 Hz, 2H, CH₂), δ 1.94–1.81 (m, 1H, CH), δ 1.77–1.34 (m, 6H, 3CH₂); ¹³CNMR(300 MHz, DMSO-d₆): 173.4798, 145.4370, 140.4961, 128.7982, 128.0911, 125.2703, 120.6140, 56.6285, 54.4179, 40.3966, 38.6180, 35.5524, 34.5898, 28.6706, 25.6814; HRMS-(ESI) m/z calcd. for C₂₁H₂₃NOS₂ [(M + H)⁺] 370.1294, found 370.1292.

[5-(1,2-dithiolan-3-yl)-N-(furan-3-ylmethyl)pentanamide] (19): R/S-LA (250 mg, 1.2 mmol) was reacted with 3-furylmethylamine (130 mg, 1.3 mmol) and DIPEA (700 µL, 4 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (605 mg, 1.6 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (100 mg), yield: 24%; mp: 52−54 ℃; 1HNMR(300 MHz, DMSO-d6): δ 8.14 (m, 1H, NH), δ 7.59 (m, 1H, CH Ar), δ 7.52 (m, 1H, CH Ar), δ 6.40 (s, 1H, CH Ar), δ 4.08 (d, J = 5.5937 Hz, 2H, CH₂), δ 3.66–3.55 (m, 1H, CH), δ 3.24–3.07 (m, 2H, CH₂), δ 2.47–2.34 (m, 1H, CH), δ 2.10 (t, J = 7.2901 Hz, 2H, CH₂), δ 1.92–1.79 (m, 1H, CH) δ 1.76–1.44 (m, 4H, CH₂), δ 1.42–1.24 (m, 2H, CH₂); ¹³CNMR(300 MHz, DMSO-d₆):172.3005, 143.7706, 140.1421, 123.8400, 111.0567, 56.5924, 40.3702, 38.5716, 35.5521, 34.5878, 33.6794, 28.7855, 25.4973; HRMS (ESI) m/z calcd. for C₁₃H₁₉NO₂S₂ [(M + H)⁺] 286.0930, found 286.0929.

[N-((2,3-dihydro-1H-inden-1-yl)methyl)-5-(1,2-dithiolan-3-yl)pentanamide] (20): R/S-LA (263 mg, 1.3 mmol) was reacted with 1-(2,3-dihydro-1H-inden-1-yl)methanamine (248 mg, 1.4 mmol) and DIPEA (700 µL, 4 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (570 mg, 1.5 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (56 mg), yield: 14%; mp: 115−118 ℃; 1HNMR(300 MHz, DMSO-d6): δ 7.30–7.12 (m, 4H, 4CH Ar), δ 5.54 (s, 1H, NH), 3.72–3.50 (m, 2H, CH₂), δ 3.48–3.31 (m, 2H, CH₂), δ 3.24–3.06 (m, 2H, CH₂), δ 3.02–2.80 (m, 2H, CH₂), δ 2.52–2.40 (m, 1H, CH), δ 2.33–2.21 (m, 1H, CH), δ 2.20–2.12 (m, 2H, CH₂), δ 1.97–1.74 (m, 1H, CH), δ 1.73–1.55 (m, 5H, 2CH₂ CH), δ 1.54–1.34 (m, 2H, CH₂); ¹³CNMR(300 MHz, CDCl₃): 172.9120, 144.4857, 143.9918, 127.0698, 126.3863, 124.8711, 123.7653, 56.4331, 44.7112, 42.7514, 40.2643, 38.5012, 36.5770, 34.6581, 31.2452, 29.5841, 28.9103, 25.4380; HRMS (ESI) m/z calcd. for C₁₈H₂₅NOS₂ [(M + H)⁺] 336.1450, found 336.1449.

[1-(4-(9H-fluoren-9-yl)piperazin-1-yl)-5-(1,2-dithiolan-3-yl)pentan-1-one] (21): R/S-LA (334 mg, 1.6 mmol) was reacted with 1-(9H-fluoren-9-yl)piperazine (483 mg, 1.9 mmol) and DIPEA (700 µL, 4 mmol) in DMF (10 mL) at room temperature for 24 h with HATU (740 mg, 1.9 mmol) as the coupling reagent. The desired product was isolated, using procedure “B”, as a yellowish solid (525 mg), yield: 83%; mp: 119−122 ℃; 1HNMR(300 MHz, DMSO-d6): δ 7.69 (d, J = 7.4277 Hz, 1H, 2CH Ar), δ 7.60 (d, J = 7.3360 Hz, 2H, 2CH Ar), δ 7.38 (t, J = 7.2443 Hz, 1H, 2CH Ar), δ 7.33–7.25 (m, 2H, 2CH Ar), δ 4.86 (s, 1H, CH), δ 3.67–3.58 (m, 2H, CH₂), δ 3.57–3.50 (m, 1H, CH), δ 3.41 (m, 2H, CH₂), δ 3.22–3.04 (m, 2H, CH₂), δ 2.73 (m, 2H, CH₂), δ 2.51–2.38 (m, 3H, CH₂ CH), δ 2.26 (t, J = 7.3818 Hz, 2H, CH₂), δ 1.96–1.82 (m, 1H, CH), δ 1.75–1.53 (m, 4H, 2CH₂), δ 1.53–1.34 (m, 2H, CH₂); ¹³CNMR(300 MHz, CDCl₃): 171.1196, 143.4397, 141.0402, 128.3107, 127.1544, 125.9073, 119.8402, 69.9317, 56.4537, 49.6125, 48.4564, 46.2708, 42.3715, 40.2410, 38.6320, 38.4939, 34.7594, 32.9358, 29.1109, 24.9850; HRMS (ESI) m/z calcd. for C₂₅H₃₀N₂OS₂ [(M + H)⁺] 439.1872, found 439.1871.

Supporting information

S1 File. SwissADME drug likeness data for all 21 compounds.

https://doi.org/10.1371/journal.pone.0352906.s001

(DOCX)

S2 File. Individual ¹H/¹³C NMR spectra for 21 compounds.

https://doi.org/10.1371/journal.pone.0352906.s002

(DOCX)

S3 File. HRMS data.

https://doi.org/10.1371/journal.pone.0352906.s003

(DOCX)

Acknowledgments

We acknowledge the “National Institute of Mental Health's Psychoactive Drug Screening Program [Contract # HHSN-271-2018-00023-C (NIMH PDSP), directed by Bryan L Roth, University of North Carolina at Chapel Hill]” for testing our compounds and providing the Ki data. We thank the “University of Texas San Antonio (UTSA) Mass Spectrometry & Proteomics Core Facility” for the HRMS data. The Author also acknowledges Dr. Osbert Ntinda Sikazwe (University of Zambia, Zambia) for inspiring me to persist in my research journey for drug molecules.

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Figures

Abstract

1 Introduction

2 Results and Discussion

2.1 Synthesis

2.2 Docking simulations

2.3 Drug likeness

2.4 Receptor binding affinities

3 Conclusion

4 Experimental

4.1 General

4.2 Chemistry

4.3 Synthetic specifics and spectral data

Supporting information

S1 File. SwissADME drug likeness data for all 21 compounds.

S2 File. Individual 1H/13C NMR spectra for 21 compounds.

S3 File. HRMS data.

Acknowledgments

References

S2 File. Individual ¹H/¹³C NMR spectra for 21 compounds.