Machine learning-based predictive models for identifying high active compounds against HIV-1 integrase.

HIV-integrase is an important drug target because it catalyzes chromosomal integration of proviral DNA towards establishing latent infection. Computer-aided drug design has immensely contributed to identifying and developing novel antiviral drugs. We have developed various machine learning-based predictive models for identifying high activity compounds against HIV-integrase. Multiclass models were built using support vector machine with reasonable accuracy on the test and evaluation sets. The developed models were evaluated by rigorous validation approaches and the best features were selected by Boruta method. As compared to the model developed from all descriptors set, a slight improvement was observed among the selected descriptors. Validated models were further used for virtual screening of potential compounds from ChemBridge library. Of the six high active compounds predicted from selected models, compounds 9103124, 6642917 and 9082952 showed the most reasonable binding-affinity and stable-interaction with HIV-integrase active-site residues Asp64, Glu152 and Asn155. This was in agreement with previous reports on the essentiality of these residues against a wide range of inhibitors. We therefore highlight the rigorosity of validated classification models for accurate prediction and ranking of high active lead drugs against HIV-integrase.

Antiproliferative activity of novel thiophene and thienopyrimidine derivatives.

A novel series of newly synthesized thiophene derivatives, ethyl-4,5-dimethyl-2-(3-(3,4,5-trimethoxyphenyl)thioureido)thiophene-3-carboxylate 3, ethyl-2-[(2-(dimethylamino)ethoxy)mercapto)methyleneamino)]-4,5-dimethyl-thiophene-3-carboxylate 9, thienopyrimidines 4, 7, 10-20, triazolothienopyrimidines 5, 6 were prepared and tested for their antiproliferative activity. The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data. The results showed that the synthesized compounds were more active on breast cancer than on colon cancer cell lines and the most potent compounds in this study are compounds 3 and 13 which exerted remarkable activity against MDA-MB-231 (breast cancer) and HT-29 (colon cancer) cell lines with IC50 values (40.68, 49.22 µM) for compound 3 and (34.04, 45.62 µM) for compound 13. Also, compounds 4-6, 9 showed a moderate activity against breast cancer cell line, while compounds 15, 19 and 20 showed no activity.

Synthesis, anticancer activity and radiosensitizing evaluation of some new 2-pyridone derivatives.

Based on the reported anticancer activity of 2-pyridone, a new series of 6-amino-5-cyano-1-(3-ethylphenyl)-2-oxo-4-substituted-1,2-dihydropyridine-3-carbo-nitriles 4a-p were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line and liver human tumor cell line (HEPG2). Radiosensitizing activity was also evaluated. The starting material 2-cyano-N-(3-ethylphenyl)-acetamide 3 was obtained via reaction of 3-ethyl aniline 1 with ethyl cyanoacetate under condition of fusion. Upon treatment of compound 3 with aromatic aldehyde and malononitrile in the presence of catalytic amount of piperidine yielded the corresponding 1,2-dihydropyridine derivative 4a-p. Also chromenes 5 and 6 were obtained in good yield via reaction of compound 3 with salicyladehyde under different condition. The chromene derivatives 5 and 6 were further reacted with malononitrile in NH4OAc, afford the corresponding chromenopyridones 7 and 8. The structures of the synthesized compounds 3-8 were confirmed by analytical and spectral data. Compounds 4d, 4e, 5 and 6 showed higher anticancer activity against EAC cell line with IC50 values (75.32, 20.77, 73.1 and 67.05 µM) compared to doxorubicin as positive control with IC50 value (68.13 µM), moreover, these compounds showed potent activity on HEPG2 cell line with IC50 values (26.5, 19.2, 39.3, 44.9 µM), respectively, compared to doxorubicin (CAS 29042-30-6) (38.46 µM) and their activity increased synergistically when combined with γ-radiation.

Ocular manifestations of branchio-oculo-facial syndrome: report of a novel mutation and review of the literature.

PURPOSE: To report unusual ocular manifestations of branchio-oculo-facial syndrome (BOFS) caused by a novel mutation in activating enhancer binding protein 2 alpha (TFAP2A). METHODS: Full ophthalmological evaluation and direct sequencing of TFAP2A. RESULTS: A 10-year-old girl with unusual ocular manifestations of BOFS such as elliptical shaped microcornea and a novel de novo TFAP2A mutation was identified. CONCLUSIONS: This report expands the ocular phenotypic spectrum of BOFS and adds to the small number of reported TFAP2A mutations.