Analogues 1a Research Articles

Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide.

Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.

On resin click-chemistry-mediated synthesis of novel enkephalin analogues with potent anti-nociceptive activity

Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This entailed the solid-phase synthesis of two enkephalin precursor chains followed by a CuI-catalyzed azide-alkyne cycloaddition, with the aim of improving in vivo analgesic efficacy versus DPDPE. NOVA2 showed good affinity and selectivity for the μ-opioid receptor (KI of 59.2 nM, EC50 of 12.9 nM, EMax of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.

Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism.

The rate of mutability of pathogenic H1N1 influenza virus is a threat. The emergence of drug resistance to the current competitive inhibitors of neuraminidase, such as oseltamivir and zanamivir, attributes to a need for an alternative approach. The design and synthesis of new analogues with alternate approach are particularly important to identify the potential neuraminidase inhibitors which may not only have better anti-influenza activity but also can withstand challenge of resistance. Five series of scaffolds, namely aurones (1a-1e), pyrimidine analogues (2a-2b), cinnamic acid analogues (3a-3k), chalcones (4a-4h) and cinnamic acid linkages (5a-5c), were designed based on virtual screening against pandemic H1N1 virus. Molecular modelling studies revealed that the designed analogues occupied 430-loop cavity of neuraminidase. Docking of sialic acid in the active site preoccupied with the docked analogues, i.e. in 430-loop cavity, resulted in displacement of sialic acid from its native pose in the catalytic cavity. The favourable analogues were synthesized and evaluated for the cytotoxicity and cytopathic effect inhibition by pandemic H1N1 virus. All the designed analogues resulting in displacement of sialic acid suggested alternate binding mechanism. Overall results indicated that aurones can be measured best among all as potential neuraminidase inhibitor against pandemic H1N1 virus.

Lapachol and synthetic derivatives: in vitro and in vivo activities against Bothrops snake venoms.

BackgroundIt is known that local tissue injuries incurred by snakebites are quickly instilled causing extensive, irreversible, tissue destruction that may include loss of limb function or even amputation. Such injuries are not completely neutralized by the available antivenins, which in general are focused on halting systemic effects. Therefore it is prudent to investigate the potential antiophidic effects of natural and synthetic compounds, perhaps combining them with serum therapy, to potentially attenuate or eliminate the adverse local and systemic effects of snake venom. This study assessed a group of quinones that are widely distributed in nature and constitute an important class of natural products that exhibit a range of biological activities. Of these quinones, lapachol is one of the most important compounds, having been first isolated in 1882 from the bark of Tabebuia avellanedae.Methodology/Principal findingsIt was investigated the ability of lapachol and some new potential active analogues based on the 2-hydroxi-naphthoquinone scaffold to antagonize important activities of Bothrops venoms (Bothrops atrox and Bothrops jararaca) under different experimental protocols in vitro and in vivo. The bioassays used to test the compounds were: procoagulant, phospholipase A2, collagenase and proteolytic activities in vitro, venom-induced hemorrhage, edematogenic, and myotoxic effects in mice. Proteolytic and collagenase activities of Bothrops atrox venom were shown to be inhibited by lapachol and its analogues 3a, 3b, 3c, 3e. The inhibition of these enzymatic activities might help to explain the effects of the analogue 3a in vivo, which decreased skin hemorrhage induced by Bothrops venom. Lapachol and the synthetic analogues 3a and 3b did not inhibit the myotoxic activity induced by Bothrops atrox venom. The negative protective effect of these compounds against the myotoxicity can be partially explained by their lack of ability to effectively inhibit phospholipase A2 venom activity. Bothrops atrox venom also induced edema, which was significantly reduced by the analogue 3a.ConclusionsThis research using a natural quinone and some related synthetic quinone compounds has shown that they exhibit antivenom activity; especially the compound 3a. The data from 3a showed a decrease in inflammatory venom effects, presumably those that are metalloproteinase-derived. Its ability to counteract such snake venom activities contributes to the search for improving the management of venomous snakebites.

Rhodium catalyzed stereospecific reductive carbocyclization of 1,6-enynes and synthesis of 4′-methyl-6′-substituted aristeromycins

The need of long-term treatment for chronic HBV, emergence of drug-resistant viruses and inefficiency of currently approved therapies to eliminate covalently closed circular DNA (cccDNA), mandates identification of potent and selective inhibitors of HBV replication with novel mechanisms of action. Entecavir, a carbocyclic guanosine nucleoside analog, is the most potent inhibitor of HBV replication on the market. Moreover, the naturally occurring carbocyclic nucleosides aristeromycin are known for their wide range of antiviral activities.In this research, we have utilized BINAP directed rhodium catalyzed reductive carbocyclization of 1,6-enynes (8a–b) through asymmetric hydrogenation which is an approach, not yet explored in carbocyclic sugar synthesis. Interestingly, we obtained exclusive anti-(9a) and Z-anti (9b) carbocyclic sugars. The new aristeromycin analogs (10a–b) with scaffold combination of entecavir and aristeromycin were then synthesized using the Mitsunobu reaction followed by deprotection.

Isolation, structural modification of macrophin from endophytic fungus Phoma macrostoma and their cytotoxic potential

Four known metabolites, macrophin (1), rosellisin (2), 2-(2-hydroxy-5-6-methoxy-3-methylene-1,4-benzodioxin-2(3H)-one (3), and methoxyphenoxyacrylic acid (4) were isolated, for the first time, from an endophytic fungus, Phoma macrostoma inhabiting the inner tissue of medicinal plant Glycyrrhiza glabra Linn. Their structures were characterized by comparison of their NMR data with literature data, and X-ray diffraction data of macrophin (1) as described herein for the first time. The compounds (1–4) were evaluated for their growth-inhibitory activities against a panel of cancer cell lines. Of these substances, macrophin (1) showed prominent cytotoxic activity against the MDA-MB-231, T47D, MCF-7, and MIAPaCa-2 cancer-cell lines with IC50 values of 14.8, 8.12, 13.0, and 0.9 μM, respectively. This biological significance has prompted us to generate a series of five acylated analogs (1a–1e) of 1 to conduct structure–activity relationship (SAR) study. The result illustrates all the analogues (1a–1e) were more potent than 1 against MDMB-231 and MIAPaCa-2 cancer cell lines. The compound 1d, an n-butanoyl substituent, has been proven to be three-fold more potent than 1 with IC50 values of 0.3 and 3.7 µM against MIAPaCa-2 and MDMB-231 cell lines, respectively.

Antiparasitic activity of synthetic curcumin monocarbonyl analogues against Trichomonas vaginalis

Trichomoniasis is a parasitic infection caused by Trichomonas vaginalis and it is considered to be the most common non-viral sexually transmitted infection in the world. Since the 1960s, nitroimidazoles such as metronidazole are the drugs of choice for the treatment of trichomoniasis, but many adverse effects and allergic reactions may result from their use. Reports of metronidazole-resistant infections also highlight the importance for the search of new anti-T. vaginalis agents. Considering this, herein we report the anti-T. vaginalis evaluation of 21 synthetic monocarbonyl analogues of curcumin, which itself has been reported to possess antiparasitic potential. From the in vitro analysis of the synthetic molecules, untreated trophozoites, and metronidazole at 100 μM, it was observed that three curcumin analogues (3a, 3e, and 5e) exhibited anti-T. vaginalis activity comparable to metronidazole (no significant statistical difference). Optimal antiparasitic concentrations were determined to be 80 μM and 90 μM for propanone derivatives 3a and 3e, respectively, and 200 μM for cyclohexanone derivative 5e. Kinetic growth curves showed that, after 24 h, the trophozoites were completely inhibited. At the tested concentrations, natural curcumin did not significantly inhibit the growth of trophozoites, therefore demonstrating that the designed synthetic molecules not only have better chemical stability, but also higher anti-T. vaginalis potential. Cytotoxicity analysis, performed on VERO cells, demonstrated low, moderate and high cytotoxic effects for analogues 3e, 5e and 3a, respectively. This study suggests that these analogues possess chemical features of interest to be further explored as alternatives for the treatment of trichomoniasis.

Synthesis of novel derivatives of 7,8-dihydro-6H-imidazo[2,1-b][1,3]benzothiazol-5-one and their virus-inhibiting activity against influenza A virus.

Influenza remains a highly pathogenic and hardly controlled human infection. The ability of selecting drug-resistant variants necessitates the search and development of novel anti-influenza drugs. Herein, we describe the synthesis and evaluation of a series of novel 2-substituted 7,8-dihydro-6H-imidazo[2,1-b][1,3]benzothiazol-5-ones 3a-k for their virus-inhibiting activity against influenza A virus. The new analogues 3a-k prepared in two steps from commercially available cyclohexane-1,3-diones were fully characterized by their NMR and mass spectral data. Among the new derivatives screened for cytotoxicity and in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells, three analogues 3i-k containing a thiophene unit were found to exhibit high virus-inhibiting activity (high SI values) and a favorable toxicity profile. The compound 3j (CC50 : >1000 μM, SI = 77) with higher potency is the best anti-influenza hit analogue for further structural optimization and drug development. The most active compounds did not inhibit viral neuraminidase and possess therefore other targets and mechanisms of activity than the currently used neuraminidase inhibitors.

A novel tetrazole analogue of resveratrol is a potent anticancer agent

A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD50 values of 4.60 µM, 0.02 µM, 1.46 µM, and 1.08 µM, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI50 values <10 nM against more than 90% of the human cancer cell lines in the 60-cell panel. Analogues 8g, 8h, 10a and 10b were also tested for their ability to inhibit the polymerization of tubulin, and compound 8h was found to be the most potent analogue. Molecular modeling studies demonstrated that 8h binds to the colchicine binding site on tubulin. Thus, compound 8h is considered to be a lead druglike molecule from this tetrazole series of compounds.

Synthesis and evaluation of chalcone analogues containing a 4-oxoquinazolin-2-yl group as potential anti-tumor agents

The chalcone motif can be found in many molecules that contribute to essential biological processes, and many chalcone-containing compounds exhibit potent anti-cancer activity. Here, we synthesized two series of chalcone analogues (3a−s and 6a−s) based on substituting the chalcone B-ring or A-ring with a 4-oxoquinazolin-2-yl group, and then evaluated them for cytotoxic activity in human colorectal HCT-116 and breast cancer MCF-7 cell lines. Compounds 3a−s (in which a 4-oxoquinazolin-2-yl group functioned as the B-ring) were markedly more cytotoxic than compounds 6a−s (in which 4-oxoquinazolin-2-yl group functioned as the A-ring), based on their IC50 values to inhibit proliferation. Compound 3f was found as the most potent among 38 analogues and the mechanism of its cytotoxicity was investigated. Flow cytometry indicated that HCT-116 cells treated with compound 3f resulted in a dose-dependent accumulation of cells in the sub-G1 phase, which is representative of apoptotic cells. Subsequent assays (including Annexin V-FITC/PI, AO-EB, MitoSOX™ Red and JC-1 staining) confirmed that 3f exposure induced apoptosis in HCT-116 cells. Immunoblotting analysis indicated that cellular exposure to 3f increased the cleavage of PARP1 and caspases 3, 7, and 9. Taken together, this novel chalcone analogue has a cytotoxic effect on cultured cancer cell-lines that is likely mediated by inducing apoptosis via the mitochondrial death pathway.

Hits-to-Lead Optimization of the Natural Compound 2,4,6-Trihydroxy-3-geranyl-acetophenone (tHGA) as a Potent LOX Inhibitor: Synthesis, Structure-Activity Relationship (SAR) Study, and Computational Assignment.

A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a–g (half maximal inhibitory concentration (IC50) values ranging from 35 μM to 95 μM) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μM) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μM, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a–g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

Novel Catechol Derivatives of Arylimidamides as Antileishmanial Agents.

Two novel bis-arylimidamide derivatives with terminal catechol moieties (9a and 10a) and two parent compounds with terminal phenyl groups (DB613 and DB884) were synthesized as dihydrobromide salts (9b and 10b). The designed compounds were hybrid molecules consisting of a catechol functionality embedded in an arylimidamide moiety. All compounds were examined for invitro antiparasitic activity upon promastigotes of Leishmania major and L.infantum as well as axenic amastigotes of L.major. It was shown that conversion of terminal phenyl groups into catechol moieties resulted in more than 10-fold improvement in potency, coupled with lower cytotoxicity against fibroblast cells, compared to the corresponding parent compounds. The furan-containing analog 9a exhibited the highest activity with submicromolar IC50 values, ranging from 0.29 to 0.36μm, which is comparable in efficacy to the reference drug amphotericin B (IC50 0.28-0.33μm). The results justify further study of this class of compounds. It seems that the combination of catechol chelating groups with potent antiparasitic agents could improve the efficacy by presenting novel hybrid compounds.

4-Hydroxy-1,2,3-triazole moiety as bioisostere of the carboxylic acid function: a novel scaffold to probe the orthosteric γ-aminobutyric acid receptor binding site

The correct application of bio(iso)steric replacement, a potent tool for the design of optimized compounds, requires the continuous development of new isosters able to respond to specific target requirements. Among carboxylic acid isosters, as the hydroxylated pentatomic heterocyclic systems, the hydroxy-1,2,3-triazole represents one of the most versatile but less investigated. With the purpose to enlarge its bioisosteric application, we report the results of a study devoted to obtain potential biomimetics of the γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS). A series of N1- and N2- functionalized 4-hydroxy-1,2,3-triazole analogues of the previous reported GABAAR ligands, including muscimol, 4-PIOL, and 4-PHP has been synthesized and characterized pharmacologically. Furthermore, this study led to development of straightforward chemical strategies directed to decorate the hydroxytriazole core scaffold, opening for further elaborative studies based on this system. The unsubstituted N1- and N2-piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues (3a, 4a) of 4-PIOL and 4-PHP showed weak affinity (high to medium micromolar range), whereas substituting the 5-position of the triazole core with a 2-naphthylmethyl or 3,3-diphenylpropyl led to binding affinities in the low micromolar range. Based on electrostatic analysis and docking studies using a α1β2γ2 GABAAR homology model we were able to rationalize the observed divergence in SAR for the series of N1- and N2- piperidin-4-yl-4-hydroxy-1,2,3-triazole analogues, offering more detailed insight into the orthosteric GABAAR binding site.

Bioactive Sesquiterpenoids from the Peeled Stems of Syringa pinnatifolia

Fourteen new sesquiterpenoids, alashanoids A-H (1, 2, and 4-9), (+)-2,9-humuladien-6-ol-8-one (3b), and five pairs of enantiomers (1 and 4-7), along with eight known analogues (3a and 10-16) were isolated from the stems of Syringa pinnatifolia. The structures were established using IR, UV, MS, and NMR data. The absolute configurations of the new compounds were resolved by X-ray diffraction, a modification of Mosher's method, and experimental and calculated ECD data analysis. The new sesquiterpenoids represent three skeletons: a rare 2,2,5,9-tetramethylbicyclo[6.3.0]-undecane (1), a humulane-type (2-8), and a caryophyllene-type (9) skeleton. Compounds 6a, 7, and 11 showed protective effects against hypoxia-induced injury to H9c2 cells at a concentration of 40 μM, and 5-7, 11, and 13 inhibited NO production in LPS-induced RAW264.7 macrophage cells with IC50 values ranging from 13.6 to 70.6 μM. These compounds decreased the TNF-α and IL-6 levels in RAW264.7 cells in a concentration-dependent manner at 20-80 μM.

Total synthesis and biological evaluation of nannocystin analogues modified at the polyketide phenyl moiety

Total synthesis of a focused set of 10 nannocystin analogues 3a–3j modified at the polyketide phenyl moiety was reported. These compounds were evaluated against three cancer cell lines. Compared with the naturally occurring congener 3a, the other synthetic variants either preserved or lose antiproliferative activity at varying degrees. Moreover, the potent analogues also displayed comparable levels of cytotoxicity toward two normal cell lines.

Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist

A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3-syn-diol and 1,3-anti-diol chemophoric moieties, e.g. 4a–d and 5a–c respectively, have been designed and synthesized starting from d-glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca2+]i release assay, 4a and 5a, when tested at 30 μM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC50 of 4a (SB70) has been determined as 6 μM which is in the same range of current benchmarks for PAR2 antagonists.

Synthetic resveratrol-curcumin hybrid derivative inhibits mitosis progression in estrogen positive MCF-7 breast cancer cells

Curcumin (1) and resveratrol (2) are bioactive natural compounds that display wide pharmacological properties, including antitumor activity. However, their clinical application has been limited due to their low solubility and bioavailability. Nevertheless, independent studies have considered these compounds as interesting prototypes for developing new chemical structures useful for anticancer therapy. Here in, we report the synthesis of novel curcumin-like hydrazide analogues (3a and 3b), and a series of curcumin-resveratrol hybrid compounds (4a–f), and the evaluation of their cytotoxic potential on three tumor cell lines MCF-7 (breast), A549 (lung), and HepG2 (liver). Cell viability was significantly reduced in all tested cell lines when compounds 4c–4e were used. The IC50 values for these compounds on MCF-7 cells were lower than those for curcumin, resveratrol, or curcumin combined with resveratrol. We evidenced that 4c promoted a drastic increase of G2/M population. The accumulation of cells in mitosis onset in treated cultures was due to, at least in part, the ability of 4c to modulate nuclear kinase proteins, which orchestrate important events in mitosis progression. We have also observed significant reduction of the relative RNAm abundance of CCNB1, PLK1, AURKA, AURKB in samples treated with 4c, with concomitant increase of CDKN1A (p21). Thus, compound 4c is a promising multi-target antitumor agent that should be considered for further in vivo studies.

Ancistrocyclinones A and B, unprecedented pentacyclic N,C-coupled naphthylisoquinoline alkaloids, from the Chinese liana Ancistrocladus tectorius.

Two unique pentacyclic N,C-coupled naphthylisoquinolines, the ancistrocyclinones A (5) and B (6), were discovered in the Chinese liana Ancistrocladus tectorius. Furthermore, six known, likewise N,C-coupled alkaloids, viz., ancistrocladinium A (7a) and its mono- and bisphenolic analogs 8a and 9a were isolated, along with their atropo-diastereomers 7b, 8b, and 9b. The stereostructures of 5 and 6 were determined by HRESIMS, 1D and 2D NMR, oxidative degradation, and ECD calculations. The pentacyclic ancistrocyclinones A (5) and B (6) are structurally similar to berberine alkaloids - yet arising from a most different biosynthetic pathway: they are apparently formed by N,C-coupling of their polyketide-derived molecular halves, followed by oxidative cyclo-condensation. Biomimetic conversion of the co-occurring 4'-O-demethylancistrocladinium A (8a) to ancistrocyclinone A (5) via a quinoid intermediate supported the postulated pathway. Ancistrocyclinone A (5) was found to significantly inhibit the viability of drug-sensitive human leukemia (CCRF-CEM) and multidrug-resistant tumor cells (CEM/ADR5000) with comparable efficacies.

Synthesis of tetrahydro-1H-indolo[2,3-b]pyrrolo[3,2-c]quinolonesviaintramolecular oxidative ring rearrangement of tetrahydro-β-carbolines and their biological evaluation

Tetrahydro-1H-indolo[2,3-b]pyrrolo[3,2-c]quinolones are synthesizedviaa unique intramolecular oxidative ring rearrangement.

Reaction of allyl bromide with cyclometallated platinum(II) complexes: Unusual kinetic behavior and a novel case of methyl and allyl C-C bond reductive elimination

Reaction of the known cyclometallated platinum(II) complexes [PtMe(CˆN)(PPh2Me)], in which CˆN is either 2-phenylpyridinate (abbreviated as ppy-H), 1a, or benzo-h-quinolate (abbreviated as bhq-H), 1b, with excess allyl bromide, CH2=CH-CH2Br, in acetone gave the thermodynamic Pt(IV) product complex cis-[PtMe(CH2-CH=CH2)Br(ppy-H)(PPh2Me)], 2a, or cis-[PtMe(CH2-CH=CH2)Br(bhq-H)(PPh2Me)], 2b, respectively, in which the phosphine and the allyl ligands are situated trans to each other. Although these Pt(IV) complexes may possibly take up other isomeric forms such as one in that allyl ligand being situated trans to N atom or one that allyl ligand is located trans to Br atom, our full characterization of the complexes using 1H, 13C and 31P NMR spectroscopy, completely ruled out the latter possibilities. Our attempt to grow crystals of the Pt(IV) complex 2a was ended up to give crystals of the Pt(II) complex [PtBr(ppy-H)(PPh2Me)], 3a, resulting from reductive elimination of Me and allyl from 2a. Also the solution of the Pt(IV) bhq-H analogous complex 2b in acetone at 60 °C gradually gave the Pt(II) complex [PtBr(bhq-H)(PPh2Me)], 3b; these two new complexes 3a and 3b were also prepared directly and fully characterized and their NMR spectra were used to confirm the occurred reductive eliminations. These observations show that during the time a novel case of Me and allyl C-C bond reductive elimination, as determined by 1H, 13C and 31P NMR spectroscopy and X-ray crystallography, is happening. Kinetics of reaction of the Pt(II) complexes 1 with excess ally bromide were investigated by UV–vis spectroscopy and found that while the bhq-H complex 1b reacts by usual second order SN2 mechanism, first order in both the complex and the reagent, the analogous ppy-H complex 1a reacts almost completely by an unusual third order kinetics, first order on 1a and second order on allyl bromide reagent. Suggestions are made for these behaviors and DFT calculations were obtained to support the experimental observations.