Publications

Eight new diaryltriazine derivatives containing 4-allylamino and 4-azido substitutes guided by molecular docking have been designed and synthesized based on our previous work. The evaluation of HIV inhibitory activity demonstrated that all compounds were potent against HIV-1 replication. The most active compound 7c exhibited activity against HIV-1 (IC50 = 0.034 micromol x L(-1), SI = 6,475) and the double mutant strain (IC50 = 9.39 micromol x L(-1)) in the micromolar range, which was more potent than nevirapine.

Novel series of niacin esters of chalcones 2, 4 and 6 were designed as antineoplastic agents that have the potential to release the chemoprotectant niacin. These enones are cytotoxic to human CD4(+ )T-lymphocyte Molt 4/C8 and CEM and murine leukemia L1210 cells. Quantitative structure-activity relationship (QSAR) studies of the biodata in series 4 revealed that cytotoxic potency was enhanced by placing electron-repelling groups in one of the aryl rings. The compounds are lethal to HL-60, HSC-2, HSC-3 and HSC-4 neoplasms but less toxic to nonmalignant hepatocyte growth factor, hematopoietic progenitor cell and human periodontal ligament fibroblast cells. Hence, the compounds display tumor-selective toxicity. These chalcones are well tolerated in mice and no overt toxicity was noted. The results establish that in general the compounds in series 2, 4 and 6 have positive characteristics which warrant further studies.

Dypiridamole (DPM) is widely used in the treatment of cardiovascular diseases as a coronary vasodilator and inhibitor of platelet aggregation. Phosphonylmethoxyethyl (PME) and 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of purines and pyrimidines are potent and selective inhibitors of varicella-zoster virus (VZV), herpes simplex virus (HSV) and human cytomegalovirus (HCMV). We have found that DPM markedly potentiates the antiviral effects of the PME derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), and of the HPMP derivatives of adenine (HPMPA), 3-deazaadenine (HPMPc 3 A) and cyclic HPMPA (cHPMPA). This was reflected by a significant decrease in the 50% inhibitory concentration of the acyclic nucleoside phosphonates for VZV-, HSV- and HCMV-induced cytopathic effect or plaque formation. DPM did not enhance the activity of vidarabine, acyclovir or ganciclovir. These results were confirmed by virus yield assays (for HSV and HCMV) and flow cytometry (for VZV).

The prototype compounds of three different classes of nucleoside phosphonates [i.e. 9-(2-phosphonomethoxyethyl)adenine (PMEA), 9-(2-phosphonomethoxyethoxy)adenine (PMEoA) and 9-[(2R,5R)-2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine (D4API)] were investigated and compared for their antiviral activities. The three test compounds showed a marked inhibition of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in CEW and MT-4 cell cultures [50% effective concentration (EC 50 ): 0.8-14μm]. D4API was 2- and 15-fold more inhibitory than PMEA and PMEoA, respectively. In contrast, the activity of PMEA against human hepatitis B virus (HHBV) in human hepatoma Hep G2 2.2.15 cells was 5- and 10-fold more pronounced than the activities of PMEoA and D4API, respectively (EC 50 1.2μm versus 10 and 6 μm, respectively). The inhibitory activity of D4API against Moloney murine sarcoma virus (MSV)-induced C3H/3T3 cell transformation was superior to the activities of PMEA and PMEoA by at least one order of magnitude (EC 50 for D4API 1.3μM, versus 2.8 and 14 μM for PMEA and PMEoA, respectively). The markedly greater inhibitory effect of D4API on MSV in vitro was in agreement with our In vivo findings that D4API inhibited MSV-induced tumour formation in newborn mice and delayed the MSV-associated animal death at a lower dose than PMEA or PMEoA. Both PMEA and D4API emerged as promising compounds that warrant further investigation for their anti-retrovirus and anti-hepadnavirus activities in vivo.

New polyanionic compounds were obtained from radical addition of thiomalic acid and mercaptopropionic acid onto perallylated cyclodextrins (CDs) under UV irradiation with a catalytic amount of alpha,alpha'-azobis(isobutyronitrile). All these polyanions, bearing 18-48 carboxylate groups, inhibited human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-4 cells at a 50% inhibitory concentration (IC50) of 0.1-2.9 microM, while not being toxic to the host cells at concentrations up to 62 microM. These compounds were also active against a clinical HIV-1 isolate (HE) at >/=4-fold higher concentrations. Only some compounds showed activity against the two HIV-2 strains (ROD and EHO) but at higher concentrations than those required to inhibit HIV-1 (IIIB and HE) replication. In addition, these compounds were not active against the M-tropic HIV-1 strain BaL but were active against simian immunodeficiency virus [SIV (MAC251)]. These compounds were also inhibitory to the replication of human cytomegalovirus at an IC50 of 1-10 microM, but not herpes simplex virus (type 1 and type 2) or other (picorna-, toga-, reo-, orthomyxo-, paramyxo-, bunya-, rhabdo-, and poxvirus) viruses. Radical addition on perallylated CDs of a protected cysteine gave polyzwitterionic compounds. None of these last compounds proved inhibitory to the replication of HIV-1, HIV-2, or any of the other viruses tested.

Five new carbocyclic nucleosides were prepared by constructing a guanine (compounds 3, 5) or 8-azaguanine (compounds 4, 6, and 7) base on the amino group of (1′S,3′R)-3-(3′-amino-2′,2′-dimethylcyclobutyl) propan-1-ol (8), and their activities against a variety of viruses and tumor cell lines were determined. Only compounds 3 and 7 showed a detectable activity at subtoxic concentrations against some viruses tested.

Human immunodeficiency virus type-1 (HIV-1) resistance severely compromises the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs). This study developed novel DAPY-derived NNRTIs via a structure-based drug design strategy with <b>K-5a2</b> as the lead. All designed compounds demonstrate potent antiviral activity against the HIV-1 wild-type (WT) strain (EC₅₀ = 3.03-21.1 nM). Notably, compound <b>19</b> was identified as the most potent inhibitor against a panel of clinically relevant mutant strains (EC₅₀ = 5.03-37.7 nM) with resistance fold (RF) values (RF = 0.746-5.59) superior to that of ETR (RF = 1.11-15.5). Mechanistic studies confirmed that <b>19</b> potently inhibits HIV-1 RT (IC₅₀ = 0.107 μM). Molecular docking and MM/GBSA calculations validate its stable binding with NNIBP, mediated by extensive hydrogen bond networks, hydrophobic interactions, and π-π stacking. Collectively, this work delivers <b>19</b> as a highly promising next-generation NNRTI lead compound with exceptional resilience against drug-resistant HIV-1.